Pharmaceutical dosage forms comprising 6&#39;-fluoro-(N-methyl- or N,N-dimethyl-)-4-phenyl-4&#39;,9&#39;-dihydro-3&#39;H-spiro[cyclohexane-1,1&#39;-pyrano[3,4,b]indol]-4-amine

ABSTRACT

A pharmaceutical dosage form for administration twice daily, once daily or less frequently, which contains 6′-fluoro-(N-methyl- or N,N-dimethyl)-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amine or a physiologically acceptable salt thereof.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority from co-pending provisional patentapplication Nos. 61/370,634; 61/370,643 and 61/370,648, each filed Aug.4, 2010, the entire disclosure of each of which is incorporated hereinby reference. Priority is also claimed based on European patentapplication nos. EP 10 008 115.7; EP 10 008 116.5 and EP 10 008 117.3,each also filed Aug. 4, 2010 and each of which is likewise incorporatedherein by reference in its entirety.

FIELD OF THE INVENTION

The invention relates to a pharmaceutical dosage form for preferablyoral administration twice daily, once daily or less frequently, whichcontains a pharmacologically active agent according to general formula(I)

wherein R is —H or —CH₃, or a physiologically acceptable salt thereof.

The invention also relates to the use of a pharmaceutical dosage formfor preferably oral administration once daily, which contains apharmacologically active agent according to general formula (I)

wherein R is —H or —CH₃, or a physiologically acceptable salt thereof,in the treatment of neuropathic pain, preferably chronic neuropathicpain.

The invention additionally relates to the use of a pharmaceutical dosageform for preferably oral administration once daily, which contains apharmacologically active agent according to general formula (I)

wherein R is —H or —CH₃, or a physiologically acceptable salt thereof,in the treatment of nociceptive pain, preferably acute or chronicnociceptive pain.

The pharmacologically active agents according to general formula (I) canalso be referred to as 6′-fluoro-(N-methyl- orN,N-dimethyl-)-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-py-rano[3,4,b]indol]-4-amine.Unless expressly stated otherwise, this term also includes thephysiologically acceptable salts.

BACKGROUND OF THE INVENTION

The pharmacologically active agents according to the invention are knownfrom the prior art and can be administered orally, perorally,parenterally, intravenously, intraperitoneally, intra-dermally,intramuscularly, intrathecally, epidurally, intranasally, buccally,rectally or locally, for example to the skin, the mucous membranes orinto the eyes. The compounds exhibit analgesic properties and areparticularly suitable for the treatment of acute, visceral, neuropathicor chronic pain (cf., e.g., WO 2004/043967 and WO 2008/040481).

Conventional analgesics are typically available as formulationsproviding immediate release or as formulations providing prolongedrelease.

On the one hand, formulations providing immediate release upon oraladministration have the advantage that they lead to a fast release ofthe analgesic in the gastrointestinal tract. As a result, acomparatively high dose of the analgesic is quickly absorbed leading tohigh plasma levels within a short period of time and resulting in arapid onset of pain relief, i.e. analgesic action begins shortly afteradministration. This is particularly desirable in acute pain.

At the same time, however, a rapid reduction in the analgesic action isusually observed, because metabolization and/or distriburion and/orexcretion of the analgesic cause a decrease of its plasma levels. Forthat reason, formulations providing immediate release of analgesicstypically need to be administered frequently, e.g. eight times per day.This is not only detrimental with respect to patient compliance but alsomay cause comparatively high peak plasma drug concentrations and highfluctuations between peak and trough plasma drug concentrations which inturn may deteriorate tolerability.

On the other hand, formulations providing prolonged release upon oraladministration have the advantage that they need to be administered lessfrequently, typically once daily or twice daily. This improves patientcompliance and also can reduce peak plasma drug concen-trations andfluctuations between peak and trough plasma drug concentrations which inturn may improve tolerability.

At the same time, however, release of the analgesic in thegastrointestinal tract is prolonged. As a result, a comparatively lowdose of the analgesic is quickly absorbed leading to low plasma levelsand resulting in a retarded onset of pain relief, i.e. analgesic actionbegins quite a while after first administration.

Furthermore, as formulations providing prolonged release typicallycontain higher doses of the analgesics than formulations providingimmediate release, they bear a higher risk of being misused. Olderpatients in particular frequently have difficulties in taking solidpharmaceutical dosage forms. Further, most elderly require adaptationsin dosages due to different ADME (absorption, distribution, metablolsmexcretion) characteristics in age which is another reason for the needof breakable tablets. To counter this problem, various apparatuses havebeen developed by means of which solid pharmaceutical dosage forms maybe comminuted or pulverized (“tablet crushers”). Such apparatuses areused, for example, by the care staff in old people's homes. Thepharmaceutical dosage forms are then administered to the people beingcared for not as tablets etc. but rather as powder, for example to getround the difficulties involved in swallowing tablets. However, thecomminution of pharmaceutical dosage forms with such apparatuses isproblematic if the pharmaceutical dosage forms are prolonged releaseformulations. As a rule, comminution then results in destruction of theinner structure of the pharmaceutical dosage form, which is responsiblefor the prolonged release, so doing away with the prolonged-releaseaction. Consequently, after administration, frequently all thephysiologically active substance originally contained in thepharmaceutical dosage form is released in a relatively short time,whereby a comparatively very high plasma concentration of the substanceis abruptly reached for a relatively short period (dose dumping). Inthis way, the original prolonged-release formulations becomeimmediate-release formulations. Depending on the physiological activityof the substance, this may cause considerable side-effects however, andin extreme cases may even lead to the death of the patient (cf., e.g.,J. E. Mitchell, Oral Pharmaceutical dosage forms That Should Not BeCrushed: 2000 Update, Hospital Pharmacy, 2000; H. Miller et al., ToCrush or Not to Crush, Nursing 2000; R. Griffith et al., Tablet Crushingand the law: the implications for nursing; Prof. Nurse 2003).Intentional chewing of prolonged-release formulations may also lead toan overdose of the substance contained therein. Sometimes patients chewthe pharmaceutical dosage forms deliberately, though often in ignoranceof the type and purpose of a prolonged-release formulation, because theyhope for a quicker effect.

Formulations providing a dual release mode, i.e. a combination ofimmediate release with prolonged release, are also known (cf., e.g., C.M. Lopez et al., Compressed Matrix Core Tablet as a Quick/SlowDual-Component Delivery System Containing Ibuprofen, AAPS PharmSciTech2007; 8(3), E1-E8). However, these formulations typically rely uponimmediate-release units and prolonged-release units that are locallyseparated from one another and therefore, such pharmaceutical dosageforms can only be prepared by specific and costly methods.

The treatment of chronic pain involves long-term analgesic treatmentwhich often requires higher doses than those sufficient in acute painepisodes. In order to keep adverse events at a tolerable level,titration of the analgesic dose may be required at the start of therapy,especially when common μ-opioid analgesics such as morphine areemployed. Accordingly, titrated long-term opioid therapy typicallystarts with sub-therapeutic doses which are gradually increased untiladequate analgesia is reported.

It is an object of the invention to provide pharmaceutical dosage formscontaining 6′-fluoro-(N-methyl- orN,N-dimethyl-)-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-aminewhich have advantages compared to the pharmaceutical dosage forms of theprior art. In particular, the pharmaceutical dosage forms should providegood bioavailability and rapid and adequate pain relief already afterthe first administration, but also should have a high tolerability, goodcompliance, and safety.

This object has been achieved by the invention as described and claimedhereinafter.

It has been found that 6′-fluoro-(N-methyl- orN,N-dimethyl-)-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-aminehas a comparatively poor water solubility. Further, it has been foundthat in spite of said poor water solubility, pharmaceutical dosage formscan be prepared which provide immediate release of 6′-fluoro-(N-methyl-orN,N-dimethyl-)-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amineand provide good bioavailability. Still further, it has been found that6′-fluoro-(N-methyl- orN,N-dimethyl-)-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-aminehas a relatively large pharmacokinetic terminal half life time(t_(1/2)≈60-90 h) and thus, provides pharmacological activity for acomparatively extended period of time after administration (theoperational half life is about 24 h). For details concerning theterminal half life and the operational half life see e.g. to S. Sahin etal., Pharm. Res., 2008, 25(12), 2869-2877.

Therefore, it has been surprisingly found that upon preferably oraladministration of the pharmaceutical dosage form containing thepharmacologically active agent according to the invention, a rapid onsetof pain relief can be achieved followed by a prolonged analgesic effect,although, or even if, the pharmaceutical dosage form provides immediaterelease. Therefore, the pharmaceutical dosage form according to theinvention combines the advantageous properties of conventionalformulations providing immediate release—e.g., rapid pain relief due toadequately high concentration of active ingredient just a short time(e.g., about one hour) after administration of the pharmaceuticalcomposition—with the advantageous properties of conventionalformulations providing prolonged release—e.g., long-lasting analgesicaction owing to an adequately high level of active ingredient over aprolonged time —, and at the same time even overcomes the drawbacks ofsaid conventional formulations. By taking the pharmacologically activeagent in the formulation according to the invention, the patient caneffectively combat his pain acutely and, at the same time, treat iteffectively over a prolonged period without further measures and merelyby regular administration at 12 (or e.g., 24) hourly intervals.

It is particularly surprising that the pharmaceutical dosage formaccording to the invention not only allows the pharmacologically activeagent to start flowing rapidly in the plasma when the pharmaceuticaldosage form is first administered, leading to a rapid onset of painrelief in the patient owing to the immediate release, but at the sametime ensures long-lasting therapeutic efficacy over a relatively longperiod (at least 12 hours, preferably at least 24 hours). Therefore, thepain suffered by a patient can rapidly be alleviated when thepharmaceutical dosage form according to the invention is administeredwithout the analgesic action quickly fading again.

Further, it has been surprisingly found that due to its largepharmacokinetic half-life, the highest plasma concentrations (peakplasma concentrations) of 6′-fluoro-(N-methyl- orN,N-dimethyl-)-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amineare increased upon once daily administration of fixed dosages. The peakconcentration (C_(max)) was observed surprisingly late, namely at about4 to 6 hours after administration.

It has been surprisingly found that once daily administration of fixed,comparatively small doses of 6′-fluoro-(N-methyl- orN,N-dimethyl-)-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amine,e.g. daily doses of 40 μg, leads to subtherapeutic peak plasmaconcentrations on the first day of therapy, but to therapeutic peakplasma concentrations later on. For example, in case of a daily dose of40 μg, a substantial analgesic effect was observed in patients withpainful diabetic neuropathy on the fourth and fifth day of once dailyadministration.

Moreover, it has been surprisingly found that at such comparativelysmall doses, the occurrence of side effects compared to morphine wasconsiderably decreased under equianalgesic conditions.

These surprising effects suggest that during long-term therapy ofneuropathic pain, preferably chronic neuropathic pain, the dose of6′-fluoro-(N-methyl- orN,N-dimethyl-)-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-aminemay generally be kept at a low level, not only initially but throughoutthe whole analgesic therapy and accordingly, undesired side-effects maybe reduced or even fully suppressed. Dose titration during the initialadministration phase may be possible but is not required necessarily.

The pharmaceutical dosage form according to the invention has goodpatient compliance and safety. Even if the pharmaceutical dosage formaccording to the invention is tampered with, e.g. by means of tabletcrushers, dose dumping cannot occur—crushing the pharmaceutical dosageform does not further accelerate the immediate release profile. Thisfinding is supported by the pharmacokinetic profiles of three differentgalenic formulations (solution in macrogol, self-emulsifying capsulesfilled with liquid, and tablets).

The invention relates to a pharmaceutical dosage form containing apharmacologically active agent according to general formula (I)

wherein R is —H or —CH₃,

or a physiologically acceptable salt thereof; said pharmaceutical dosageform being for administration twice daily, once daily or lessfrequently.

The invention also relates to a pharmaceutical dosage form foradministration once daily and containing a pharmacologically activeagent according to general formula (I)

wherein R is —H or —CH₃,or a physiologically acceptable salt thereof,

-   -   which provides immediate release in vitro of the        pharmacologically active agent according to general formula (I)        in accordance with Ph. Eur.; and    -   which contains the pharmacologically active agent according to        general formula (I) in a dose of from 10 μg to 190 μg; and    -   wherein the pharmacokinetic parameter T_(max) is within the        range of from 0.5 to 16 h,        for use in the treatment of neuropathic pain, preferably chronic        neuropathic pain.

The invention additionally relates to a pharmaceutical dosage form foradministration once daily and containing a pharmacologically activeagent according to general formula (I)

wherein R is —H or —CH₃,or a physiologically acceptable salt thereof,

-   -   which provides immediate release in vitro of the        pharmacologically active agent according to general formula (I)        in accordance with Ph. Eur.; and    -   which contains the pharmacologically active agent according to        general formula (I) in a dose of from 150 μg to 800 μg,        preferably more than 190 μg to 800 μg; and    -   wherein the pharmacokinetic parameter T_(max) is within the        range of from 0.5 to 16 h,        for use in the treatment of nociceptive pain, preferably acute        or chronic nociceptive pain.

Unless expressly stated otherwise, all dosages concerning thepharmacologically active agent according to the invention are preferablyexpressed as weight equivalent dosages based upon the free base.

The pharmacologically active agent according to general formula (I) canalso be referred to as“6′-fluoro-N-methyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amine”when R is —H, and“6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclo-hexane-1,1′-pyrano[3,4,b]indol]-4-amine”when R is —CH₃; for the purpose of the specification, thepharmacologically active agent according to general formula (I) can alsobe referred to as “6′-fluoro-(N-methyl- orN,N-dimethyl-)-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amine”.

In a preferred embodiment, the pharmacologically active agent accordingto general formula (I) has a stereochemistry according to generalformula (I′)

wherein R is —H or —CH₃, or a physiologically acceptable salt thereof.

In another embodiment of the pharmaceutical dosage form according to theinvention, the compound of formula (I) is selected from

in the form of the free base or a physiologically acceptable saltthereof.

The free base according to general formula (I′a) can be systematicallyreferred to as“1,1-(3-methylamino-3-phenylpentamethylene)-6-fluoro-1,3,4,9-tetrahydropyrano[3,4-b]indole(trans)” or as“(1r,40-6′-fluoro-N-methyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amine”,respectively.

The free base according to general formula (I′b) can be systematicallyreferred to as“1,1-(3-dimethylamino-3-phenylpentamethylene)-6-fluoro-1,3,4,9-tetrahydropyrano[3,4-b]indole(trans)” or as“(1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amine”,respectively.

The definition of the pharmacologically active agent according togeneral formula (I) as used herein includes 6′-fluoro-(N-methyl- orN,N-dimethyl-)-4-phenyl-4′,9′-dihydro-3′H-spiro-[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amine,derivatives thereof and stereoisomers thereof in any possible form,thereby particularly including solvates and polymorphs, salts, inparticular acid addition salts and corresponding solvates andpolymorphs.

In a preferred embodiment, the pharmacologically active agent accordingto general formula (I) is present as the single diastereomer accordingto general formula (I′).

In another preferred embodiment the pharmacologically active agentaccording to general formula (I) is present as mixture of diastereomers.Such a mixture may contain the diastereomers in any ratio. Adiastereomeric mixture could, for example, contain the diastereomers ina ratio of 60±5:40±5, 70±5:30±5, 80±5:20±5 or 90±5:10±5. Preferably, thepharmaceutical dosage form according to the invention contains thediastereomer according to general formula (I′) in a diastereomericexcess (de) of at least 50% de, more preferably at least 60% de, stillmore preferably at least 70% de, yet more preferably at least 80% de,even more preferably at least 90% de, most preferably at least 95% de,and in particular at least 98% de, with respect to the otherdiastereomer (i.e. trans vs. cis and anti vs. syn, respectively).

6′-fluoro-(N-methyl- orN,N-dimethyl-)-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyra-no[3,4,b]indol]-4-aminemay be present in the pharmaceutical dosage form according to theinvention in form of the free base or in form of an acid addition salt,whereby any suitable acid capable of forming such an addition salt maybe used.

The conversion of 6′-fluoro-(N-methyl- orN,N-dimethyl-)-4-phenyl-4′,9′-dihydro-3′H-spiro-[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amineinto a corresponding addition salt, for example, via reaction with asuitable acid may be effected in a manner well known to those skilled inthe art. Suitable acids include but are not limited to hydrochloricacid, hydrobromic acid, sulfuric acid, methanesulfonic acid, formicacid, acetic acid, oxalic acid, succinic acid, tartaric acid, mandelicacid, fumaric acid, lactic acid, citric acid, glutamic acid and/oraspartic acid. Salt formation is preferably effected in a solvent, forexample, diethyl ether, diisopropyl ether, alkyl acetates, acetoneand/or 2-butanone. Moreover, trimethylchlorosilane in aqueous solutionis also suitable for the preparation of hydrochlorides.

The pharmacologically active agent according to general formula (I) ispreferably contained in the pharmaceutical dosage form in atherapeutically effective amount, i.e., in an amount that istherapeutically effective with regard to a daily administration of thedosage form in the treatment of pain, particularly in the treatment ofneuropathic pain, especially chronic neuropathic pain, or in thetreatment of nociceptive pain, particularly acute or chronic nociceptivepain. The amount that constitutes a therapeutically effective amountvaries according to the compound, the condition being treated, theseverity of said condition, the patient being treated, and whether thepharmaceutical dosage form is designed for an immediate or retardedrelease.

In another preferred embodiment, the pharmacologically active agentaccording to general formula (I) is contained in the dosage form in aquantity such that single administration of the dosage form does notlead to any analgesic effect, i.e. the pharmacologically active agentaccording to general formula (I) is contained in the dosage form in anamount that is sub-therapeutic with regard to a single administration ofthe dosage form. Preferably, however, once daily administration of thedosage form leads to an analgesic effect, at the latest, on the fifthday, more preferably at the latest on the fourth day and still morepreferably at the latest on the third day of once daily administration.

In an especially preferred embodiment, with respect to the treatment ofneuropathic pain, preferably chronic neuropathic pain, once dailyadministration of the dosage form leads to a sub-therapeutic plasmaconcentration of the pharmacologically active agent on the first day ofadministration, but to therapeutic plasma concentrations of thepharmacologically active agent after once daily administration of thedosage form for at least 3, or at least 4, or at least 5 subsequentdays.

In one preferred embodiment, the pharmacologically active agentaccording to general formula (I) is contained in the dosage form in aquantity such that the dosage form is not effective in the treatment ofacute pain, i.e. the pharmacologically active agent is contained in aquantity that is sub-therapeutic with regard to acute pain treatment.Preferably, the quantity is so low that even after repeatedadministration for several consecutive days, e.g. 5 days, a significanteffect in the treatment of acute pain is not achieved.

In another especially preferred embodiment, with respect to thetreatment of nociceptive pain, preferably acute or chronic nociceptivepain, once daily administration of the dosage form leads to asub-therapeutic plasma concentration of the pharmacologically activeagent on the first day of administration, but to therapeutic plasmaconcentrations of the pharmacologically active agent after once dailyadministration of the dosage form for at least 3, or at least 4, or atleast 5 subsequent days.

Preferably, the pharmacologically active agent according to generalformula (I) is contained in the dosage form in a quantity such thatinitial dose titration is not required.

Preferably, the pharmacologically active agent according to generalformula (I) is contained in the dosage form in a quantity such thatadverse events that occur during administration of the dosage form aredecreased compared to a dosage form comprising a pure μ-opioid receptoragonist, such as morphine in equianalgetic doses.

In a preferred embodiment, the content of the pharmacologically activeagent according to the general formula (I) in the pharmaceutical dosageform according to the invention is at most 95 wt.-%, more preferably atmost 50 wt.-%, yet more preferably at most 25 wt.-%, still morepreferably at most 10 wt.-%, even more preferably at most 5 wt.-%, mostpreferably at most 1.0 wt.-%, and in particular at most 0.5 wt-%.

In another preferred embodiment, the content of the pharmacologicallyactive agent according to the general formula (I) in the pharmaceuticaldosage form according to the invention is at least 0.001 wt.-%, morepreferably at least 0.005 wt.-%, yet more preferably at least 0.01wt.-%, still more preferably at least 0.05 wt.-%, even more preferablyat least 0.1 wt.-%, most preferably at least 0.5 wt.-%, and inparticular at least 1.0 wt.-%.

In another preferred embodiment, the content of the pharmacologicallyactive agent according to the general formula (I) in the pharmaceuticaldosage form according to the invention is within the range of 0.4±0.3wt.-%, for example, 0.4±0.2 wt.-%, or even 0.4±0.1 wt.-%.

In another preferred embodiment, the content of the pharmacologicallyactive agent according to the general formula (I) in the pharmaceuticaldosage form according to the invention is within the range of 0.5±0.3wt.-%, for example, 0.5±0.2 wt.-%, or even 0.5±0.1 wt.-%.

In still another preferred embodiment, the content of thepharmacologically active agent according to the general formula (I) inthe pharmaceutical dosage form according to the invention is within therange of 0.3±0.3 wt-%, for example, 0.320±0.315 wt.-%, more preferably0.320±0.310 wt.-%, still more preferably 0.320±0.305 wt.-%, yet morepreferably 0.320±0.300 wt.-%, even more preferably 0.320±0.295 wt.-%,most preferably 0.320±0.290 wt.-%, and in particular 0.320±0.285 wt.-%.

In yet another preferred embodiment, the content of thepharmacologically active agent according to the general formula (I) inthe pharmaceutical dosage form according to the invention is within therange of 0.04±0.035 wt.-%, more preferably 0.04±0.03 wt.-%, still morepreferably 0.04±0.025 wt.-%, yet more preferably 0.04±0.02 wt.-%, evenmore preferably 0.04±0.015 wt.-%, most preferably 0.04±0.01 wt.-%, andin particular 0.04±0.005 wt.-%.

In another preferred embodiment, the content of the pharmacologicallyactive agent according to the general formula (I) in the pharmaceuticaldosage form according to the invention is within the range of 0.6±0.35wt.-%, more preferably 0.6±0.3 wt.-%, still more preferably 0.6±0.25wt.-%, yet more preferably 0.6±0.2 wt.-%, even more preferably 0.6±0.15wt.-%, most preferably 0.6±0.1 wt.-%, and in particular 0.6±0.05 wt.-%.

Unless explicitly stated otherwise, in the meaning of the presentinvention the indication “wt.-%” shall mean weight of the respectiveingredient per total weight of the pharmaceutical dosage form. In casethat the pharmaceutical dosage form is film coated or encapsulated by anencapsulating medium which does not contain any amount of thepharmacologically active agent according to the general formula (I) andsurrounds a core that in turn contains the total amount of thepharmacologically active agent according to the general formula (I), theindication “wt.-%” shall mean weight of the respective ingredient pertotal weight of the composition forming said core.

When the pharmaceutical dosage form is encapsulated or film coated, thepharmacologically active agent according to general formula (I) ispreferably homogeneously distributed in the core of the pharmaceuticaldosage form. Preferably, the encapsulating medium or film coating doesnot contain any pharmacologically active agent according to generalformula (I).

In one preferred embodiment of the invention the dose of thepharmacologically active agent according to general formula (I)preferably is in the range of 0.1 μg to 5000 μg, more preferably in therange of 0.1 μg to 1000 μg, and most preferably in the range of 1.0 μgto 100 μg or in the range of 30 μg to 600 μg.

In a preferred embodiment, the content of the pharmacologically activeagent according to general formula (I) in the pharmaceutical dosage formis within the range of 25±20 μg, more preferably 25±15 μg, still morepreferably 25±10 μg, and most preferably 25±5 μg.

In another preferred embodiment, the content of the pharmacologicallyactive agent according to general formula (I) in the pharmaceuticaldosage form is within the range of 40±35 μg, more preferably 40±30 μg,still more preferably 40±25 μg, yet more preferably 40±20 μg, even morepreferably 40±15 μg, most preferably 40±10 μg, and in particular 40±5μg.

In still another preferred embodiment, the content of thepharmacologically active agent according to general formula (I) in thepharmaceutical dosage form is within the range of 50±35 μg, morepreferably 50±30 μg, still more preferably 50±25 μg, yet more preferably50±20 μg, even more preferably 50±15 μg, most preferably 50±10 μg, andin particular 50±5 μg.

In yet another preferred embodiment, the content of thepharmacologically active agent according to general formula (I) in thepharmaceutical dosage form is within the range of 60±35 μg, morepreferably 60±30 μg, still more preferably 60±25 μg, yet more preferably60±20 μg, even more preferably 60±15 μg, most preferably 60±10 μg, andin particular 60±5 μg.

In another preferred embodiment, the content of the pharmacologicallyactive agent according to general formula (I) in the pharmaceuticaldosage form is within the range of 100±90 μg, more preferably 100±80 μg,still more preferably 100±60 μg, yet more preferably 100±40 μg, evenmore preferably 100±20 μg, most preferably 100±10 μg, and in particular100±5 μg.

In still another preferred embodiment, the content of thepharmacologically active agent according to general formula (I) in thepharmaceutical dosage form is within the range of 200±175 μg, morepreferably 200±150 μg, still more preferably 200±125 μg, yet morepreferably 200±100 μg, even more preferably 200±75 μg, most preferably200±50 μg, and in particular 200±25 μg.

In yet another preferred embodiment, the content of thepharmacologically active agent according to general formula (I) in thepharmaceutical dosage form is within the range of 400±350 μg, morepreferably 400±300 μg, still more preferably 400±250 μg, yet morepreferably 400±200 μg, even more preferably 400±150 μg, most preferably400±100 μg, and in particular 400±50 μg.

In yet another preferred embodiment, the content of thepharmacologically active agent according to general formula (I) in thepharmaceutical dosage form is within the range of 600±350 μg, morepreferably 600±300 μg, still more preferably 600±250 μg, yet morepreferably 600±200 μg, even more preferably 600±150 μg, most preferably600±100 μg, and in particular 600±50 μg.

In a preferred embodiment the pharmaceutical dosage form is for use inthe treatment of acute pain, where the dose of the pharmacologicallyactive agent according to general formula (I) preferably is in the rangeof 50 μg to 3000 μg, more preferably in the range of 100 μg to 1000 μg,even more preferably in the range of 300 μg to 500 μg, and mostpreferably in the range of 350 μg to 450 μg.

In another preferred embodiment, the pharmaceutical dosage form is foruse in the treatment of acute pain, where the dose of thepharmacologically active agent according to general formula (I)preferably is in the range of 200 μg to 400 μg, and in particular in therange of 250 μg to 350 μg.

For the purpose of the specification, the wording “being for use in thetreatment of pain” is equivalent with “being adapted for use in thetreatment of pain”.

In a preferred embodiment, the pharmaceutical dosage form is for use inthe treatment of acute pain, where the dose of the pharmacologicallyactive agent according to general formula (I) preferably is in the rangeof 200 μg to 400 μg, and in particular in the range of 250 μg to 350 μg.

In a preferred embodiment, the pharmaceutical dosage form is for use inthe treatment of acute pain, where the dose of the pharmacologicallyactive agent according to general formula (I) preferably is in the rangeof 250 μg to 450 μg, and in particular in the range of 300 μg to 400 μg.

In another preferred embodiment, the pharmaceutical dosage form is foruse in the treatment of acute pain, where the dose of thepharmacologically active agent according to general formula (I)preferably is in the range of 300 μg to 500 μg, and in particular in therange of 350 μg to 450 μg.

In yet another preferred embodiment, the pharmaceutical dosage form isfor use in the treatment of acute pain, where the dose of thepharmacologically active agent according to general formula (I)preferably is in the range of 350 μg to 550 μg, and in particular in therange of 400 μg to 500 μg.

In even another preferred embodiment, the pharmaceutical dosage form isfor use in the treatment of acute pain, where the dose of thepharmacologically active agent according to general formula (I)preferably is in the range of 400 μg to 600 μg, and in particular in therange of 450 μg to 550 μg.

In another preferred embodiment the pharmaceutical dosage form is foruse in the treatment of chronic pain, where the dose of thepharmacologically active agent according to general formula (I)preferably is in the range of 0.1 μg to 500 μg, more preferably in therange of 1 μg to 250 μg, even more preferably in the range of 5 μg to100 μg, and most preferably in the range of 10 μg to 50 μg.

In a preferred embodiment, the pharmaceutical dosage form according tothe invention is for oral administration, i.e. the pharmaceutical dosageform is adapted for oral administration. Suitable alternative pathwaysof administration of the pharmaceutical dosage form according to theinvention include but are not limited to vaginal and rectaladministration.

The pharmaceutical dosage form according to the invention is foradministration twice daily, once daily or less frequently, i.e. thepharmaceutical dosage form is adapted for administration twice daily,once daily or less frequently.

In a preferred embodiment, the pharmaceutical dosage form according tothe invention is for administration twice daily.

For the purpose of the specification, “administration twice daily” (bid)preferably means that the pharmaceutical dosage form is adapted forbeing administered according to a regimen comprising the administrationof a first pharmaceutical dosage form according to the invention and thesubsequent administration of a second pharmaceutical dosage formaccording to the invention, wherein both, the first and the secondpharmaceutical dosage form are administered during a time interval ofabout 24 hours, but wherein the second pharmaceutical dosage form isadministered not earlier than 6 hours, preferably not earlier than 8hours, more preferably not earlier than 10 hours and in particular,about 12 hours after the first pharmaceutical dosage form has beenadministered.

In another preferred embodiment, the pharmaceutical dosage formaccording to the invention is for administration once daily.

For the purpose of the specification, “administration once daily” (sid)preferably means that the pharmaceutical dosage form is adapted forbeing administered according to a regimen comprising the administrationof a first pharmaceutical dosage form according to the invention and thesubsequent administration of a second pharmaceutical dosage formaccording to the invention, wherein both, the first and the secondpharmaceutical dosage form are administered during a time interval ofabout 48 hours, but wherein the second pharmaceutical dosage form isadministered not earlier than 18 hours, preferably not earlier than 20hours, more preferably not earlier than 22 hours and in particular,about 24 hours after the first pharmaceutical dosage form has beenadministered.

In another preferred embodiment, the pharmaceutical dosage formaccording to the invention is for administration once daily or lessfrequently.

In another preferred embodiment, the pharmaceutical dosage formaccording to the invention is for administration less frequently thanonce daily, preferably thrice during four days (3/4), twice during threedays (2/3), thrice during five days (3/5), once during two days (1/2),thrice in a week (3/7), twice during five days (2/5), once during threedays (1/3), twice in a week (2/7), once during four days (1/4), onceduring five days (1/5), once during six days (1/6), or once in a week(1/7). According to this embodiment, administration once during two days(1/2) is particularly preferred.

A skilled person is fully aware that administration regimens “twicedaily, once daily, or less frequently” may be realized by administeringa single pharmaceutical dosage form containing the full amount of thepharmacologically active agent according to general formula (I) to beadministered at a particular point in time or, alternatively,administering a multitude of dose units, i.e. two, three or more doseunits, the sum of which multitude of dose units containing the fullamount of the pharmacologically active agent according to generalformula (I) to be administered at said particular point in time, wherethe individual dose units are for simultaneous administration oradministration within a short period of time, e.g. within 5, 10 or 15minutes.

In another preferred embodiment of the invention, the dosage formaccording to the invention is adapted for administration once daily andcontains the pharmacologically active agent according to general formula(I) in a dose of from 10 μg to 190 μg, i.e. the dosage form according tothe invention contains the pharmacologically active agent according togeneral formula (I) in a daily dose of from 10 μg to 190 μg.

In a preferred embodiment, the dose of the pharmacologically activeagent according to general formula (I) preferably is in the range offrom 10 μg to 180 μg, preferably in the range of from 12.5 μg to 150 μg,more preferably in the range of from 15 μg to 120 μg, still morepreferably in the range of from 17.5 μg to 100 μg, yet more preferablyin the range of from 20 μg to 90 μg, most preferably in the range offrom 25 μg to 80 μg, and in particular in the range of from 30 μg to 75μg.

In a preferred embodiment, the dose of the pharmacologically activeagent according to general formula (I) is in the range of from 10 μg to50 μg.

In a preferred embodiment, the dose of the pharmacologically activeagent according to general formula (I) is in the range of from 1.0 μg to100 μg.

In a preferred embodiment, the content of the pharmacologically activeagent according to general formula (I) in the pharmaceutical dosage formis within the range of 30±20 μg, more preferably 30±15 μg, mostpreferably 30±10 μg, and in particular 30±5 μg. In another preferredembodiment, the content of the pharmacologically active agent accordingto general formula (I) in the pharmaceutical dosage form is within therange of 35±25 μg, more preferably 35±20 μg, still more preferably 35±15μg, most preferably 35±10 μg, and in particular 35±5 μg. In a preferredembodiment, the content of the pharmacologically active agent accordingto general formula (I) in the pharmaceutical dosage form is within therange of 40±30 μg, more preferably 40±25 μg, still more preferably 40±20μg, yet more preferably 40±15 μg, most preferably 40±10 μg, and inparticular 40±5 μg. In another preferred embodiment, the content of thepharmacologically active agent according to general formula (I) in thepharmaceutical dosage form is within the range of 45±35 μg, morepreferably 45±30 μg, still more preferably 45±25 μg, yet more preferably45±20 μg, even more preferably 45±15 μg, most preferably 45±10 μg, andin particular 45±5 μg. In still another preferred embodiment, thecontent of the pharmacologically active agent according to generalformula (I) in the pharmaceutical dosage form is within the range of50±35 μg, more preferably 50±30 μg, still more preferably 50±25 μg, yetmore preferably 50±20 μg, even more preferably 50±15 μg, most preferably50±10 μg, and in particular 50±5 μg. In yet another preferredembodiment, the content of the pharmacologically active agent accordingto general formula (I) in the pharmaceutical dosage form is within therange of 55±35 μg, more preferably 55±30 μg, still more preferably 55±25μg, yet more preferably 55±20 μg, even more preferably 55±15 μg, mostpreferably 55±10 μg, and in particular 55±5 μg. In a preferredembodiment, the content of the pharmacologically active agent accordingto general formula (I) in the pharmaceutical dosage form is within therange of 60±40 μg or 60±35 μg, more preferably 60±30 μg, still morepreferably 60±25 μg, yet more preferably 60±20 μg, even more preferably60±15 μg, most preferably 60±10 μg, and in particular 60±5 μg. Inanother preferred embodiment, the content of the pharmacologicallyactive agent according to general formula (I) in the pharmaceuticaldosage form is within the range of 65±40 μg or 65±35 μg, more preferably65±30 μg, still more preferably 65±25 μg, yet more preferably 65±20 μg,even more preferably 65±15 μg, most preferably 65±10 μg, and inparticular 65±5 μg. In still another preferred embodiment, the contentof the pharmacologically active agent according to general formula (I)in the pharmaceutical dosage form is within the range of 70±40 μg or70±35 μg, more preferably 70±30 μg, still more preferably 70±25 μg, yetmore preferably 70±20 μg, even more preferably 70±15 μg, most preferably70±10 μg, and in particular 70±5 μg. In yet another preferredembodiment, the content of the pharmacologically active agent accordingto general formula (I) in the pharmaceutical dosage form is within therange of 75±40 μg or 75±35 μg, more preferably 75±30 μg, still morepreferably 75±25 μg, yet more preferably 75±20 μg, even more preferably75±15 μg, most preferably 75±10 μg, and in particular 75±5 μg. In apreferred embodiment, the content of the pharmacologically active agentaccording to general formula (I) in the pharmaceutical dosage form iswithin the range of 80±45 μg or 80±40 μg, more preferably 80±35 μg or80±30 μg, still more preferably 80±25 μg, yet more preferably 80±20 μg,even more preferably 80±15 μg, most preferably 80±10 μg, and inparticular 80±5 μg. In another preferred embodiment, the content of thepharmacologically active agent according to general formula (I) in thepharmaceutical dosage form is within the range of 85±45 μg or 85±40 μg,more preferably 85±35 μg or 85±30 μg, still more preferably 85±25 μg,yet more preferably 85±20 μg, even more preferably 85±15 μg, mostpreferably 85±10 μg, and in particular 85±5 μg. In still anotherpreferred embodiment, the content of the pharmacologically active agentaccording to general formula (I) in the pharmaceutical dosage form iswithin the range of 90±45 μg or 90±40 μg, more preferably 90±35 μg or90±30 μg, still more preferably 90±25 μg, yet more preferably 90±20 μg,even more preferably 90±15 μg, most preferably 90±10 μg, and inparticular 90±5 μg. In yet another preferred embodiment, the content ofthe pharmacologically active agent according to general formula (I) inthe pharmaceutical dosage form is within the range of 95±35 μg, morepreferably 95±30 μg, still more preferably 95±25 μg, yet more preferably95±20 μg, even more preferably 95±15 μg, most preferably 95±10 μg, andin particular 95±5 μg. In a preferred embodiment, the content of thepharmacologically active agent according to general formula (I) in thepharmaceutical dosage form is within the range of 100±80 μg, morepreferably 100±60 μg, still more preferably 100±40 μg, even morepreferably 100±20 μg, most preferably 100±10 μg, and in particular 100±5μg. In another preferred embodiment, the content of thepharmacologically active agent according to general formula (I) in thepharmaceutical dosage form is within the range of 110±35 μg, morepreferably 110±30 μg, still more preferably 110±25 μg, yet morepreferably 110±20 μg, even more preferably 110±15 μg, most preferably110±10 μg, and in particular 110±5 μg. In still another preferredembodiment, the content of the pharmacologically active agent accordingto general formula (I) in the pharmaceutical dosage form is within therange of 120±60 μg, more preferably 120±50 μg, still more preferably120±40 μg, yet more preferably 120±30 μg, even more preferably 120±20μg, most preferably 120±10 μg, and in particular 120±5 μg. In stillanother preferred embodiment, the content of the pharmacologicallyactive agent according to general formula (I) in the pharmaceuticaldosage form is within the range of 130±60 μg, more preferably 130±50 μg,still more preferably 130±40 μg, yet more preferably 130±30 μg, evenmore preferably 130±20 μg, most preferably 130±10 μg, and in particular130±5 μg. In yet another preferred embodiment, the content of thepharmacologically active agent according to general formula (I) in thepharmaceutical dosage form is within the range of 140±50 μg, morepreferably 140±50 μg, still more preferably 140±40 μg, yet morepreferably 140±30 μg, even more preferably 140±20 μg, most preferably140±10 μg, and in particular 140±5 μg. In still another preferredembodiment, the content of the pharmacologically active agent accordingto general formula (I) in the pharmaceutical dosage form is within therange of 150±60 μg, more preferably 150±50 μg, still more preferably150±40 μg, yet more preferably 150±30 μg, even more preferably 150±20μg, most preferably 150±10 μg, and in particular 150±5 μg. In apreferred embodiment, the content of the pharmacologically active agentaccording to general formula (I) in the pharmaceutical dosage form iswithin the range of 160±30 μg, more preferably 160±25 μg, still morepreferably 160±20 μg, yet more preferably 160±15 μg, most preferably160±10 μg, and in particular 160±5 μg. In another preferred embodiment,the content of the pharmacologically active agent according to generalformula (I) in the pharmaceutical dosage form is within the range of170±20 μg, more preferably 170±10 μg, and in particular 170±5 μg.

In a preferred embodiment, the pharmaceutical dosage form according tothe invention is adapted for oral administration. Suitable alternativepathways of administration of the pharmaceutical dosage form accordingto the invention include but are not limited to vaginal and rectaladministration.

In one preferred embodiment, the pharmaceutical dosage form according tothe invention is intended for administration once daily.

For the purpose of the specification, “administration once daily” (sid,OD) preferably means that the pharmaceutical dosage form is adapted forbeing administered according to a regimen comprising the administrationof a first pharmaceutical dosage form according to the invention and thesubsequent administration of a second pharmaceutical dosage formaccording to the invention, wherein both, the first and the secondpharmaceutical dosage form are administered during a time interval ofabout 48 hours, but wherein the second pharmaceutical dosage form isadministered not earlier than 18 hours, preferably not earlier than 20hours, more preferably not earlier than 22 hours and in particular,about 24 hours after the first pharmaceutical dosage form has beenadministered.

A skilled person is fully aware that administration regimens “oncedaily” may be realized by administering a single pharmaceutical dosageform containing the full amount of the pharmacologically active agentaccording to general formula (I) to be administered at a particularpoint in time or, alternatively, administering a multitude of doseunits, i.e. two, three or more dose units, the sum of which multitude ofdose units containing the full amount of the pharmacologically activeagent according to general formula (I) to be administered at saidparticular point in time, where the individual dose units are adaptedfor simultaneous administration or administration within a short periodof time, e.g. within 5, 10 or 15 minutes.

The dosage form according to the invention is for use in the treatmentof neuropathic pain, preferably chronic neuropathic pain such asdiabetic neuropathic pain. Preferably, the pain is moderate, severe, ormoderate to severe.

For the purpose of the specification, neuropathic pain is pain thatoriginates from nerve damage or nerve malfunction. Preferably, theneuropathic pain is selected from acute neuropathic pain and chronicneuropathic pain. Neuropathic pain may be caused by damage or diseaseaffecting the central or peripheral portions of the nervous systeminvolved in bodily feelings (the somatosensory system). Preferably, thedosage form according to the invention is for use in the treatment ofchronic neuropathic pain or acute neuropathic pain, peripheralneuropathic pain or central neuropathic pain, mononeuropathic pain orpolyneuropathic pain. When the neuropathic pain is chronic, it may bechronic peripheral neuropathic pain or chronic central neuropathic pain,in a preferred embodiment chronic peripheral mononeuropathic pain orchronic central mononeuropathic pain, in another preferred embodimentchronic peripheral polyneuropathic pain or chronic centralpolyneuropathic pain. When the neuropathic pain is acute, it may beacute peripheral neuropathic pain or acute central neuropathic pain, ina preferred embodiment acute peripheral mononeuropathic pain or acutecentral mononeuropathic pain, in another preferred embodiment acuteperipheral polyneuropathic pain or acute central polyneuropathic pain.The invention also relates to a pharmacologically active agent accordingto general formula (I) or a physiologically acceptable salt thereof foruse in the treatment of neuropathic pain as described above, preferablyby means of administering once daily the pharmaceutical dosage formaccording to the invention.

Central neuropathic pain is found in spinal cord injury, multiplesclerosis, and some strokes. Fibromyalgia is potentially a central paindisorder and is responsive to medications that are effective forneuropathic pain. Aside from diabetic neuropathy and other metabolicconditions, the common causes of painful peripheral neuropathies areherpes zoster infection, HIV-related neuropathies, nutritionaldeficiencies, toxins, remote manifestations of malignancies, genetic,and immune mediated disorders or physical trauma to a nerve trunk.Neuropathic pain is common in cancer as a direct result of cancer onperipheral nerves (e.g., compression by a tumor), or as a side effect ofchemotherapy, radiation injury or surgery.

In another preferred embodiment, the pain to be treated is selected fromthe group consisting of pain being or being associated with panicdisorder [episodic paroxysmal anxiety] [F41.0]; dissociative[conversion] disorders [F44]; persistent somatoform pain disorder[F45.4]; pain disorders exclusively related to psychological factors[F45.41]; nonorganic dyspareunia [F52.6]; other enduring personalitychanges [F62.8]; sadomasochism [F65.5]; elaboration of physical symptomsfor psychological reasons [F68.0]; migraine [G43]; other headachesyndromes [G44]; trigeminal neuralgia [G50.0]; atypical facial pain[G50.1]; phantom limb syndrome with pain [G54.6]; phantom limb syndromewithout pain [G54.7]; acute and chronic pain, not elsewhere classified[G89]; ocular pain [H57.1]; otalgia [H92.0]; angina pectoris,unspecified [120.9]; other specified disorders of nose and nasal sinuses[J34.8]; other diseases of pharynx [J39.2]; temporomandibular jointdisorders [K07.6]; other specified disorders of teeth and supportingstructures [K08.8]; other specified diseases of jaws [K10.8]; other andunspecified lesions of oral mucosa [K13.7]; glossodynia [K14.6]; otherspecified diseases of anus and rectum [K62.8]; pain in joint [M25.5];shoulder pain [M25.51]; sacrococcygeal disorders, not elsewhereclassified [M53.3]; spine pain [M54.]; radiculopathy [M54.1];cervicalgia [M54.2]; sciatica [M54.3]; low back pain [M54.5]; pain inthoracic spine [M54.6]; other dorsalgia [M54.8]; dorsalgia, unspecified[M54.9]; other shoulder lesions [M75.8]; other soft tissue disorders,not elsewhere classified [M79]; myalgia [M79.1]; neuralgia and neuritis,unspecified [M79.2]; pain in limb [M79.6]; other specified disorders ofbone [M89.8]; unspecified renal colic [N23]; other specified disordersof penis [N48.8]; other specified disorders of male genital organs[N50.8]; mastodynia [N64.4]; pain and other conditions associated withfemale genital organs and menstrual cycle [N94]; mittelschmerz [N94.0];other specified conditions associated with female genital organs andmenstrual cycle [N94.8]; pain in throat and chest [R07]; pain in throat[R07.0]; chest pain on breathing [R07.1]; precordial pain [R07.2]; otherchest pain [R07.3]; chest pain, unspecified [R07.4]; abdominal andpelvic pain [R10]; acute abdomen pain [R10.0]; pain localized to upperabdomen [R10.1]; pelvic and perineal pain [R10.2]; pain localized toother parts of lower abdomen [R10.3]; other and unspecified abdominalpain [R10.4]; flatulence and related conditions [R14]; abdominalrigidity [R19.3]; other and unspecified disturbances of skin sensation[R20.8]; pain associated with micturition [R30]; other and unspecifiedsymptoms and signs involving the urinary system [R39.8]; headache [R51];pain, not elsewhere classified [R52]; acute pain [R52.0]; chronicintractable pain [R52.1]; other chronic pain [R52.2]; pain, unspecified[R52.9]; other complications of cardiac and vascular prosthetic devices,implants and grafts [T82.8]; other complications of genitourinaryprosthetic devices, implants and grafts [T83.8]; other complications ofinternal orthopaedic prosthetic devices, implants and grafts [T84.8];other complications of internal prosthetic devices, implants and grafts,not elsewhere classified [T85.8]; wherein the information in bracketsrefers to the classification according to ICD-10.

The invention also relates to a pharmacologically active agent accordingto general formula (I) or a physiologically acceptable salt thereof foruse in the treatment of pain, preferably neuropathic pain as describedabove, preferably by means of administering once daily thepharmaceutical dosage form according to the invention.

In accordance with another preferred embodiment, the dosage formaccording to the invention is adapted for administration once daily andcontains the pharmacologically active agent according to general formula(I) in a dose of from 150 μg to 800 μg, preferably more than 190 μg to800 μg, i.e. the dosage form according to the invention contains thepharmacologically active agent according to general formula (I) in adaily dose of from 150 μg to 800 μg.

In a preferred embodiment, the dose of the pharmacologically activeagent according to general formula (I) preferably is in the range offrom 200 μg to 800 μg, preferably in the range of from 210 μg to 750 μg,more preferably in the range of from 220 μg to 700 μg, still morepreferably in the range of from 230 μg to 650 μg, yet more preferably inthe range of from 240 μg to 600 μg, and most preferably in the range offrom 250 μg to 550 μg.

In a preferred embodiment, the dose of the pharmacologically activeagent according to general formula (I) is in the range of from 200 μg to600 μg. In a preferred embodiment, the dose of the pharmacologicallyactive agent according to general formula (I) is in the range of from300 μg to 500 μg.

In a preferred embodiment, the content of the pharmacologically activeagent according to general formula (I) in the pharmaceutical dosage formis within the range of 200±50 μg, more preferably 200±40 μg, mostpreferably 200±30 μg, and in particular 200±20 μg. In another preferredembodiment, the content of the pharmacologically active agent accordingto general formula (I) in the pharmaceutical dosage form is within therange of 250±100 μg, more preferably 250±80 μg, most preferably 250±60μg, and in particular 250±50 μg. In another preferred embodiment, thecontent of the pharmacologically active agent according to generalformula (I) in the pharmaceutical dosage form is within the range of300±150 μg, more preferably 300±125 μg, most preferably 300±100 μg, andin particular 300±50 μg. In another preferred embodiment, the content ofthe pharmacologically active agent according to general formula (I) inthe pharmaceutical dosage form is within the range of 350±200 μg, morepreferably 350±175 μg, still more preferably 350±150 μg, most preferably350±100 μg, and in particular 350±50 μg. In a preferred embodiment, thecontent of the pharmacologically active agent according to generalformula (I) in the pharmaceutical dosage form is within the range of400±250 μg, more preferably 400±225 μg, still more preferably 400±200μg, yet more preferably 400±150 μg, most preferably 400±100 μg, and inparticular 400±50 μg. In another preferred embodiment, the content ofthe pharmacologically active agent according to general formula (I) inthe pharmaceutical dosage form is within the range of 450±300 μg, morepreferably 450±275 μg, still more preferably 450±250 μg, yet morepreferably 450±200 μg, even more preferably 450±150 μg, most preferably450±100 μg, and in particular 450±50 μg. In still another preferredembodiment, the content of the pharmacologically active agent accordingto general formula (I) in the pharmaceutical dosage form is within therange of 500±350 μg, more preferably 500±300 μg, still more preferably500±250 μg, yet more preferably 500±200 μg, even more preferably 500±150μg, most preferably 500±100 μg, and in particular 500±50 μg. In yetanother preferred embodiment, the content of the pharmacologicallyactive agent according to general formula (I) in the pharmaceuticaldosage form is within the range of 550±350 μg, more preferably 550±300μg, still more preferably 550±250 μg, yet more preferably 550±200 μg,even more preferably 550±150 μg, most preferably 550±100 μg, and inparticular 550±50 μg. In a preferred embodiment, the content of thepharmacologically active agent according to general formula (I) in thepharmaceutical dosage form is within the range of 600±400 μg or 600±350μg, more preferably 600±300 μg, still more preferably 600±250 μg, yetmore preferably 600±200 μg, even more preferably 600±150 μg, mostpreferably 600±100 μg, and in particular 600±50 μg.

In a preferred embodiment, the pharmaceutical dosage form according tothe invention is adapted for oral administration. Suitable alternativepathways of administration of the pharmaceutical dosage form accordingto the invention include but are not limited to vaginal and rectaladministration.

The pharmaceutical dosage form according to the invention is intendedfor administration once daily.

For the purpose of the specification, “administration once daily” (sid,OD) preferably means that the pharmaceutical dosage form is adapted forbeing administered according to a regimen comprising the administrationof a first pharmaceutical dosage form according to the invention and thesubsequent administration of a second pharmaceutical dosage formaccording to the invention, wherein both, the first and the secondpharmaceutical dosage form are administered during a time interval ofabout 48 hours, but wherein the second pharmaceutical dosage form isadministered not earlier than 18 hours, preferably not earlier than 20hours, more preferably not earlier than 22 hours and in particular,about 24 hours after the first pharmaceutical dosage form has beenadministered.

A skilled person is fully aware that administration regimens “oncedaily” may be realized by administering a single pharmaceutical dosageform containing the full amount of the pharmacologically active agentaccording to general formula (I) to be administered at a particularpoint in time or, alternatively, administering a multitude of doseunits, i.e. two, three or more dose units, the sum of which multitude ofdose units containing the full amount of the pharmacologically activeagent according to general formula (I) to be administered at saidparticular point in time, where the individual dose units are adaptedfor simultaneous administration or administration within a short periodof time, e.g. within 5, 10 or 15 minutes.

The dosage form according to the invention is for use in the treatmentof nociceptive pain, preferably acute or chronic nociceptive pain.Preferably, the pain is moderate, severe, or moderate to severe.

Nociceptive pain refers to the discomfort that results when a stimuluscauses tissue damage to the muscles, bones, skin or internal organs. Forthe purpose of the specification, nociceptive pain is caused bystimulation of peripheral nerve fibers that respond only to stimuliapproaching or exceeding harmful intensity (nociceptors), and may beclassified according to the mode of noxious stimulation; the most commoncategories being “thermal” (heat or cold), “mechanical” (crushing,tearing, etc.) and “chemical” (iodine in a cut, chili powder in theeyes). Nociceptive pain may also be divided into “visceral,” “deepsomatic” and “superficial somatic” pain.

Visceral pain describes a type of nociceptive pain originating in thebody's internal organs or their surrounding tissues. This form of painusually results from the infiltration of harmful cells, as well as thecompression or extension of healthy cells. Patients suffering fromvisceral pain tend to feel generally achy, as this pain tends to not belocalized to a specific area. Cancer is a common source of visceralpain.

Somatic pain is nociceptive pain that results from some injury to thebody. It's generally localized to the affected area and abates when thebody repairs the damage to that area. Deep somatic pain is initiated bystimulation of nociceptors in ligaments, tendons, bones, blood vessels,fasciae and muscles, and is dull, aching, poorly-localized pain.Examples include sprains and broken bones. Superficial pain is initiatedby activation of nociceptors in the skin or superficial tissues, and issharp, well-defined and clearly located.

According to the invention, nociceptive pain is preferably classifiedchronic if it has occurred for at least 3 months. Preferably, thechronic nociceptive pain is selected from chronic visceral pain, chronicdeep somatic pain and chronic superficial somatic pain.

Common causes of nociceptive pain include broken or fractured bones,bruises, burns, cuts, inflammation (from infection or arthritis), andsprains. Thus, nociceptive pain includes post-operative pain, cancerpain, low back pain, osteoarthitic pain, and inflammatory pain.

In another preferred embodiment, the pain to be treated is selected fromthe group consisting of pain being or being associated with panicdisorder [episodic paroxysmal anxiety] [F41.0]; dissociative[conversion] disorders [F44]; persistent somatoform pain disorder[F45.4]; pain disorders exclusively related to psychological factors[F45.41]; nonorganic dyspareunia [F52.6]; other enduring personalitychanges [F62.8]; sadomasochism [F65.5]; elaboration of physical symptomsfor psychological reasons [F68.0]; migraine [G43]; other headachesyndromes [G44]; trigeminal neuralgia [G50.0]; atypical facial pain[G50.1]; phantom limb syndrome with pain [G54.6]; phantom limb syndromewithout pain [G54.7]; acute and chronic pain, not elsewhere classified[G89]; ocular pain [H57.1]; otalgia [H92.0]; angina pectoris,unspecified [120.9]; other specified disorders of nose and nasal sinuses[J34.8]; other diseases of pharynx [J39.2]; temporomandibular jointdisorders [K07.6]; other specified disorders of teeth and supportingstructures [K08.8]; other specified diseases of jaws [K10.8]; other andunspecified lesions of oral mucosa [K13.7]; glossodynia [K14.6]; otherspecified diseases of anus and rectum [K62.8]; pain in joint [M25.5];shoulder pain [M25.51]; sacrococcygeal disorders, not elsewhereclassified [M53.3]; spine pain [M54.]; radiculopathy [M54.1];cervicalgia [M54.2]; sciatica [M54.3]; low back pain [M54.5]; pain inthoracic spine [M54.6]; other dorsalgia [M54.8]; dorsalgia, unspecified[M54.9]; other shoulder lesions [M75.8]; other soft tissue disorders,not elsewhere classified [M79]; myalgia [M79.1]; neuralgia and neuritis,unspecified [M79.2]; pain in limb [M79.6]; other specified disorders ofbone [M89.8]; unspecified renal colic [N23]; other specified disordersof penis [N48.8]; other specified disorders of male genital organs[N50.8]; mastodynia [N64.4]; pain and other conditions associated withfemale genital organs and menstrual cycle [N94]; mittelschmerz [N94.0];other specified conditions associated with female genital organs andmenstrual cycle [N94.8]; pain in throat and chest [R07]; pain in throat[R07.0]; chest pain on breathing [R07.1]; precordial pain [R07.2]; otherchest pain [R07.3]; chest pain, unspecified [R07.4]; abdominal andpelvic pain [R10]; acute abdomen pain [R10.0]; pain localized to upperabdomen [R10.1]; pelvic and perineal pain [R10.2]; pain localized toother parts of lower abdomen [R10.3]; other and unspecified abdominalpain [R10.4]; flatulence and related conditions [R14]; abdominalrigidity [R19.3]; other and unspecified disturbances of skin sensation[R20.8]; pain associated with micturition [R30]; other and unspecifiedsymptoms and signs involving the urinary system [R39.8]; headache [R51];pain, not elsewhere classified [R52]; acute pain [R52.0]; chronicintractable pain [R52.1]; other chronic pain [R52.2]; pain, unspecified[R52.9]; other complications of cardiac and vascular prosthetic devices,implants and grafts [T82.8]; other complications of genitourinaryprosthetic devices, implants and grafts [T83.8]; other complications ofinternal orthopaedic prosthetic devices, implants and grafts [T84.8];other complications of internal prosthetic devices, implants and grafts,not elsewhere classified [T85.8]; wherein the information in bracketsrefers to the classification according to ICD-10. The invention alsorelates to a pharmacologically active agent according to general formula(I) or a physiologically acceptable salt thereof for use in thetreatment of pain, preferably neuropathic pain as described above,preferably by means of administering once daily the pharmaceuticaldosage form according to the invention.

Preferably, the pharmaceutical dosage form according to the inventionprovides immediate release of the pharmacologically active agentaccording to general formula (I). Preferably, the pharmaceutical dosageform is specifically designed to provide immediate release of thepharmacologically active agent according to general formula (I) in vitroin accordance with Ph. Eur. When the pharmaceutical dosage form iscoated, e.g., with a coating that is soluble in gastric juice, therelease kinetic is preferably monitored after such coating has beendissolved.

For the purpose of specification, the term “immediate release” refers toany release profile that fulfills at least one, preferably both, of thefollowing requirements. First, the pharmaceutical dosage formdisintegrates in 10 minutes or less following exposure to adisintegrating medium. Methods to determine the disintegration time areknown to a person skilled in the art. For instance, they can bedetermined according to the USP XXIV disintegration test procedure,using, for example, an Erweka ZT-71 disintegration tester. Second, thepharmaceutical dosage form releases at least 70 wt.-% of the drug within15 minutes following exposure to a dissolution medium. Preferably, thein vitro release properties of the pharmaceutical dosage form accordingto the invention are determined according to the paddle method withsinker at 50, 75 or 100 rpm, preferably under in vitro conditions at37±0.5° C. in 900 mL artificial gastric juice at pH 1.2, or under thesame conditions in non-artificial gastric juice.

In a preferred embodiment, the pharmaceutical dosage form releases underin vitro conditions in 900 mL artificial gastric juice at pH 1.2 and37±0.5° C. after 30 minutes according to the paddle method with sinkerat 100 rpm at least 50 wt.-%, more preferably at least 60 wt.-%, stillmore preferably at least 70 wt.-%, yet more preferably at least 80wt.-%, most preferably at least 90 wt.-%, and in particular at least 95wt.-% of the pharmacologically active agent according to general formula(I), based on the total amount of the pharmacologically active agentaccording to general formula (I) originally contained in thepharmaceutical dosage form.

The pharmaceutical dosage form according to the invention exhibitsexcellent shelf-life and storage stability, i.e. neither the chemicalcomposition, nor the physical characteristics, nor the dissolutionprofile of the pharmaceutical dosage form are altered significantly uponstorage.

In a preferred embodiment, the pharmaceutical dosage form according tothe invention provides sufficient stability to the pharmacologicallyactive agent according to general formula (I) contained therein, so thatafter storage of the pharmaceutical dosage form at 40±2° C. at 75% RH±5%for a minimum time period of 6 weeks, preferably 3 months, theconcentrations of undesirable degradants and impurities, respectively,preferably resulting from a degradation or decomposition of thepharmacologically active agent according to general formula (I) as such,is at most 1.0 wt.-%, more preferably at most 0.8 wt.-%, still morepreferably at most 0.6 wt.-%, yet more preferably at most 0.4 wt.-%,even more preferably at most 0.2 wt.-%, most preferably at most 0.1wt.-%, and in particular at most 0.05 wt.-%, relative to the originalcontent of the pharmacologically active agent according to generalformula (I) in the pharmaceutical dosage form, i.e. its content beforesubjecting the pharmaceutical dosage form to storage.

It has been found that the pharmacologically active agent according togeneral formula (I) may be decomposed by elimination of the group —NRCH₃thereby yielding6′-fluoro-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohex-3-ene-1,1′-pyrano[3,4-b]indole]which appears to be pharmacologically inactive. Preferably, afterstorage of the pharmaceutical dosage form at 40±2° C. and 75% RH±5%, orat 25±2° C. and 60% RH±5%, for a minimum time period of 6 weeks,preferably 3 months, the concentration of6′-fluoro-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohex-3-ene-1,1′-pyrano[3,4-b]indole]is at most 1.0 wt.-%, more preferably at most 0.8 wt.-%, still morepreferably at most 0.6 wt.-%, yet more preferably at most 0.4 wt.-%,even more preferably at most 0.2 wt.-%, most preferably at most 0.1wt.-%, and in particular at most 0.05 wt.-%, relative to the originalcontent of the pharmacologically active agent according to generalformula (I) in the pharmaceutical dosage form, i.e. its content beforesubjecting the pharmaceutical dosage form to storage.

A generally accepted accelerated test for the determination of a drug'sstability according to ICH and FDA guidelines relates to the storage ofa pharmaceutical formulation containing the drug (e.g., in its containerand packaging). According to the ICH guidelines, a so-called acceleratedstorage testing should be conducted for pharmaceutical formulations at40±2° C. at 75% RH±5% for a minimum time period of 6 months.Additionally, a so-called long-term storage testing should be conductedfor pharmaceutical formulations at 25±2° C. at not less than 60% RH±5%for a minimum time period of 12 months. In case that all criteria havebeen met for the accelerated storage testing and long-term storagetesting conditions during the 6-months period, the long-time storagetesting may be shortened to 6 months and the corresponding data doubledto obtain estimated data for the 12-month period.

During the storage, samples of the pharmaceutical formulation arewithdrawn at specified time intervals and analyzed in terms of theirdrug content, presence of impurities, their release profile and ifapplicable other parameters. According to the ICH guidelines, in allsamples the purity of the drug should be ≧98%, the drug content shouldbe 95-105% (FDA guideline: 90-110%). Furthermore, the pharmaceuticalformulation should release >80% of the drug within 30 minutes.

In case of dosages forms such as tablets and capsules that contain lessthan 50 mg of a drug, a content uniformity test should additionally beconducted for 10 randomly chosen dosage forms. The pharmaceuticalformulation complies if none individual content is outside the limits of85% to 115% of the average content. In case that an individual contentis outside these limits, another 30 dosage forms have to be analyzed.The preparation fails to comply with the test if more than 3 individualcontents are outside the limits of 85 to 115% of the average content orif one or more individual contents are outside the limits of 75% to 125%of the average content.

In a preferred embodiment, after storage of the pharmaceutical dosageform for 6 months under long-term storage conditions (25° C. and 60%relative humidity) in a sealed glass container, the degradation of thepharmacologically active agent according to general formula (I) does notexceed 2.0%, more preferably 1.5%, still more preferably 1.0%, and mostpreferably 0.5%.

In another preferred embodiment, after storage of the pharmaceuticaldosage form for 6 months under accelerated storage conditions (40° C.and 75% relative humidity) in a sealed glass container, the degradationof the pharmacologically active agent according to general formula (I)does not exceed 4%, more preferably 3%, still more preferably 2%, yetmore preferably 1%, and most preferably 0.5%.

Preferably, after storage of the pharmaceutical dosage form for 6 monthsunder long-term storage conditions (25° C. and 60% relative humidity),the pharmaceutical dosage form releases under in vitro conditions in 900mL artificial gastric juice at pH 1.2 and 37±0.5° C. after 30 minutesaccording to the paddle method with sinker at 100 rpm at least 50 wt.-%,more preferably at least 60 wt.-%, still more preferably at least 70wt.-%, and most preferably at least 80 wt.-% of the pharmacologicallyactive agent according to general formula (I), based on the total amountof the pharmacologically active agent according to general formula (I)originally contained in the pharmaceutical dosage form.

Preferably, after storage of the pharmaceutical dosage form for 6 monthsunder accelerated storage conditions (40° C. and 75% relative humidity),the pharmaceutical dosage form releases under in vitro conditions in 900mL artificial gastric juice at pH 1.2 and 37±0.5° C. after 30 minutesaccording to the paddle method with sinker at 100 rpm at least 50 wt.-%,more preferably at least 60 wt.-%, still more preferably at least 70wt.-%, and most preferably at least 80 wt.-% of the pharmacologicallyactive agent according to general formula (I), based on the total amountof the pharmacologically active agent according to general formula (I)originally contained in the pharmaceutical dosage form.

The absorption properties of a pharmacologically active agentadministered by a pharmaceutical dosage form can be described by thepharmacokinetic parameters C_(max), t_(max) and AUC_(0-t). Thedetermination of C_(max) and t_(max), as well as the calculation of anAUC are well known to a person skilled in the art and described, forexample, in Bauer, Frömming, Fuhrer, “Lehrbuch der PharmazeutischenTechnologie,” 6th Edition (1999), and in Shargel, Wu-Pong, Yu, “AppliedBiopharmaceuticals & Pharmacokinetics”, 5^(th) Edition (2005). Unlessexpressly stated otherwise, all pharmacokinetic parameters are expressedas mean values over a population of subjects.

There is experimental evidence indicating that AUC_(0-t) and C_(max) ofthe pharmacologically active agent according to general formula (I) areproportional to the dose.

For the purpose of the specification, C_(max) is the highest plasmaconcentration of the pharmacologically active agent reached after singleadministration of the pharmaceutical dosage form.

For the purpose of the specification, t_(max) is the time needed inorder to reach C_(max). Preferably, unless expressly stated otherwise,T_(max) and C_(max) refer to the pharmacokinetic parameters that areobserved after a single administration of the dosage form according tothe invention to a subject that has not been treated with thepharmacologically active agent according to general formula (I) before(i.e. C_(max)═C_(max, 1 day) and t_(max)=t_(max, 1 day)).

For the purpose of the specification, C_(max, n days) is the highestplasma concentration of the pharmacologically active agent reached afteronce daily administration of the pharmaceutical dosage form for nconsecutive days, wherein n can be e.g. 1, 2, 3, 4, 5, 6, etc.

For the purpose of the specification, C_(max, ≧5 days) is the highestplasma concentration of the pharmacologically active agent reached afteronce daily administration of the pharmaceutical dosage form for at least5 consecutive days. In a preferred embodiment, steady state conditionsare reached after 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 or moredays, i.e. continuing administration of the dosage form according to theinvention on additional consecutive days does not substantially increaseC_(max) any further.

For the purpose of the specification, t_(max, n days) is the time neededto reach C_(max, n days) (post-dose), wherein n can be e.g. 1, 2, 3, 4,5, 6, etc.

For the purpose of the specification, t_(max, ≧5 days) is the timeneeded to reach C_(max, ≧5 days) (post-dose).

For the purpose of the specification, AUC_(0-t) is the area under thecurve after single administration to the time t of the last sample thatcontained an analytically quantifiable concentration of thepharmacologically active agent.

For the purpose of the specification, AUC_(0-72h) is the area under thecurve baseline after single administration to 72 hours thereafter.

In accordance with one advantageous embodiment of the invention theratio C_(max)/dose is preferably within the range of from 0.01 to 3.00m⁻³, yet more preferably within the range of from 0.02 to 2.50 m⁻³, morepreferably within the range of from 0.04 to 2.00 m⁻³, and mostpreferably within the range of from 0.06 to 1.69 m⁻³. In a preferredembodiment, the ratio C_(max)/dose is within the range of 0.40±0.35 m⁻³,more preferably 0.40±0.30 m⁻³, still more preferably 0.40±0.25 m⁻³, yetmore preferably 0.40±0.20 m⁻³, even more preferably 0.40±0.15 m⁻³, mostpreferably 0.40±0.10 m⁻³, and in particular 0.40±0.05 m⁻³. In anotherpreferred embodiment, the ratio C_(max)/dose is within the range of0.80±0.70 m⁻³, more preferably 0.80±0.60 m⁻³, still more preferably0.80±0.50 m⁻³, yet more preferably 0.80±0.40 m⁻³, even more preferably0.80±0.30 m⁻³, most preferably 0.80±0.20 m⁻³, and in particular0.80±0.10 m⁻³. In still another preferred embodiment, the ratioC_(max)/dose is within the range of 1.20±1.05 m⁻³, more preferably1.20±0.90 m⁻³, still more preferably 1.20±0.75 m⁻³, yet more preferably1.20±0.60 m⁻³, even more preferably 1.20±0.45 m⁻³, most preferably1.20±0.30 m⁻³, and in particular 1.20±0.15 m⁻³.

Preferably, t_(max) is within the range of from 15 minutes to 24 h,still more preferably within the range of from 20 minutes to 20 h, yetmore preferably within the range of from 0.5 to 16 h, most preferablywithin the range of from 1 to 12 h, and in particular within the rangeof from 2 to 10 h. In a preferred embodiment, T_(max) is within therange of 4±3.5 h, more preferably 4±3 h, still more preferably 4±2.5 h,yet more preferably 4±2 h, even more preferably 4±1.5 h, most preferably4±1 h, and in particular 4±0.5 h. In another preferred embodiment,t_(max) is within the range of 8±7 h, more preferably 8±6 h, still morepreferably 8±5 h, yet more preferably 8±4 h, even more preferably 8±3 h,most preferably 8±2 h, and in particular 8±1 h. In still anotherpreferred embodiment, t_(max) is within the range of 12±11 h, morepreferably 12±9 h, still more preferably 12±7 h, yet more preferably12±5 h, even more preferably 12±3 h, most preferably 12±2 h, and inparticular 12±1 h.

Preferably, the ratio AUC_(0-t)/dose is within the range from 0.3 to 20h/m³, more preferably within the range of from 0.4 to 18 h/m³, stillmore preferably within the range of from 0.5 to 16.5 h/m³ and mostpreferably within the range of from 0.55 to 12.5 h/m^(s). In a preferredembodiment, the ratio AUC_(0-t)/dose is within the range of 3±2.5 h/m³,more preferably 3±2 h/m³, still more preferably 3±1.5 h/m³, yet morepreferably 3±1 h/m³, even more preferably 3±0.75 h/m³, most preferably3±0.5 h/m³, and in particular 3±0.25 h/m³. In another preferredembodiment, the ratio AUC_(0-t)/dose is within the range of 6±5 h/m³,more preferably 6±4 h/m³, still more preferably 6±3 h/m³, yet morepreferably 6±2 h/m³, even more preferably 6±1.5 h/m³, most preferably6±1 h/m³, and in particular 6±0.5 h/m³. In still another preferredembodiment, the ratio AUC_(0-t)/dose is within the range of 9±8 h/m³,more preferably 9±7 h/m³, still more preferably 9±5 h/m³, yet morepreferably 9±4 h/m³, even more preferably 9±3 h/m³, most preferably 9±2h/m³, and in particular 9±1 h/m³.

In accordance with another preferred embodiment, C_(max) mayadvantageously be within the range of from 1 to 250 μg/m³, morepreferably within the range of from 5 to 200 μg/m³, still morepreferably within the range of from 10 to 150 μg/m³, most preferablywithin the range of from 15 to 120 μg/m³, and in particular within therange of from 20 to 100 μg/m³.

In a preferred embodiment, C_(max) is within the range of 20±17.5 μg/m³,more preferably within the range of 20±15 μg/m³, still more preferablywithin the range of 20±12.5 μg/m³, yet more preferably within the rangeof 20±10 μg/m³, and most preferably within the range of 20±5 μg/m³. Inanother preferred embodiment, C_(max) is within the range of 25±20μg/m³, more preferably within the range of 25±17.5 μg/m³, still morepreferably within the range of 25±15 μg/m³, yet more preferably withinthe range of 25±12.5 μg/m³, most preferably within the range of 25±10μg/m³, and in particular within the range of 25±5 μg/m³. In stillanother preferred embodiment, C_(max) is within the range of 30±20μg/m³, more preferably within the range of 30±17.5 μg/m³, still morepreferably within the range of 30±15 μg/m³, yet more preferably withinthe range of 30±12.5 μg/m³, most preferably within the range of 30±10μg/m³, and in particular within the range of 30±5 μg/m³. In yet anotherpreferred embodiment, C_(max) is within the range of 35±20 μg/m³, morepreferably within the range of 35±17.5 μg/m³, still more preferablywithin the range of 35±15 μg/m³, yet more preferably within the range of35±12.5 μg/m³, most preferably within the range of 35±10 μg/m³, and inparticular within the range of 35±5 μg/m³. In a preferred embodiment,C_(max) is within the range of 40±35 μg/m³, more preferably within therange of 40±30 μg/m³, still more preferably within the range of 40±25μg/m³, yet more preferably within the range of 40±20 μg/m³, mostpreferably within the range of 40±15 μg/m³, and in particular within therange of 40±10 μg/m³. In another preferred embodiment, C_(max) is withinthe range of 50±40 μg/m³, more preferably within the range of 50±30μg/m³, still more preferably within the range of 50±25 μg/m³, yet morepreferably within the range of 50±20 μg/m³, most preferably within therange of 50±15 μg/m³, and in particular within the range of 50±10 μg/m³.In still another preferred embodiment, C_(max) is within the range of60±40 μg/m³, more preferably within the range of 60±30 μg/m³, still morepreferably within the range of 60±25 μg/m³, yet more preferably withinthe range of 60±20 μg/m³, most preferably within the range of 60±15μg/m³, and in particular within the range of 60±10 μg/m³. In yet anotherpreferred embodiment, C_(max) is within the range of 70±45 μg/m³, morepreferably within the range of 70±40 μg/m³, still more preferably withinthe range of 70±30 μg/m³, yet more preferably within the range of 70±25μg/m³, even more preferably within the range of 70±20 μg/m³, mostpreferably within the range of 70±15 μg/m³, and in particular within therange of 70±10 μg/m³. In another preferred embodiment, C_(max) is withinthe range of 80±50 μg/m³, more preferably within the range of 80±40μg/m³, still more preferably within the range of 80±30 μg/m³, yet morepreferably within the range of 80±25 μg/m³, even more preferably withinthe range of 80±20 μg/m³, most preferably within the range of 80±15μg/m³, and in particular within the range of 80±10 μg/m³. In a preferredembodiment, C_(max) is within the range of 90±50 μg/m³, more preferablywithin the range of 90±30 μg/m³, still more preferably within the rangeof 90±25 μg/m³, yet more preferably within the range of 90±20 μg/m³,most preferably within the range of 90±15 μg/m³, and in particularwithin the range of 90±10 μg/m³. In another preferred embodiment,C_(max) is within the range of 100±50 μg/m³, more preferably within therange of 100±30 μg/m³, still more preferably within the range of 100±25μg/m³, yet more preferably within the range of 100±20 μg/m³, mostpreferably within the range of 100±15 μg/m³, and in particular withinthe range of 100±10 μg/m³. In still another preferred embodiment,C_(max) is within the range of 120±50 μg/m³, more preferably within therange of 120±30 μg/m³, still more preferably within the range of 120±25μg/m³, yet more preferably within the range of 120±20 μg/m³, mostpreferably within the range of 120±15 μg/m³, and in particular withinthe range of 120±10 μg/m³.

Preferably, the ratio C_(max)/dose is within the range of from 0.01 to3.00 m⁻³, yet more preferably within the range of from 0.02 to 2.50 m⁻³,more preferably within the range of from 0.04 to 2.00 m⁻³, and mostpreferably within the range of from 0.06 to 1.69 m⁻³.

In a preferred embodiment, the ratio C_(max)/dose is within the range of0.30±0.25 m⁻³, more preferably 0.30±0.20 m⁻³, still more preferably0.30±0.15 m⁻³, most preferably 0.30±0.10 m⁻³, and in particular0.30±0.05 m⁻³. In another preferred embodiment, the ratio C_(max)/doseis within the range of 0.40±0.35 m⁻³, more preferably 0.40±0.30 m⁻³,still more preferably 0.40±0.25 m⁻³, yet more preferably 0.40±0.20 m⁻³,even more preferably 0.40±0.15 m⁻³, most preferably 0.40±0.10 m⁻³, andin particular 0.40±0.05 m⁻³. In still another preferred embodiment, theratio C_(max)/dose is within the range of 0.50±0.35 m⁻³, more preferably0.50±0.30 m⁻³, still more preferably 0.50±0.25 m⁻³, yet more preferably0.50±0.20 m⁻³, even more preferably 0.50±0.15 m⁻³, most preferably0.50±0.10 m⁻³, and in particular 0.50±0.05 m⁻³. In yet another preferredembodiment, the ratio C_(max)/dose is within the range of 0.60±0.40 m⁻³,more preferably 0.60±0.30 m⁻³, still more preferably 0.60±0.25 m⁻³, yetmore preferably 0.60±0.20 m⁻³, most preferably 0.60±0.15 m⁻³, and inparticular 0.60±0.10 m⁻³. In even another preferred embodiment, theratio C_(max)/dose is within the range of 0.70±0.40 m⁻³, more preferably0.70±0.35 m⁻³, still more preferably 0.70±0.30 m⁻³, yet more preferably0.70±0.25 m⁻³, even more preferably 0.70±0.20 m⁻³, most preferably0.70±0.15 m⁻³, and in particular 0.70±0.10 m⁻³. In a preferredembodiment, the ratio C_(max)/dose is within the range of 0.80±0.70 m⁻³,more preferably 0.80±0.60 m⁻³, still more preferably 0.80±0.50 m⁻³, yetmore preferably 0.80±0.40 m⁻³, even more preferably 0.80±0.30 m⁻³, mostpreferably 0.80±0.20 m⁻³, and in particular 0.80±0.10 m⁻³. In anotherpreferred embodiment, the ratio C_(max)/dose is within the range of0.90±0.70 m⁻³, more preferably 0.90±0.60 m⁻³, still more preferably0.90±0.50 m⁻³, yet more preferably 0.90±0.40 m⁻³, even more preferably0.90±0.30 m⁻³, most preferably 0.90±0.20 m⁻³, and in particular0.90±0.10 m⁻³. In still another preferred embodiment, the ratioC_(max)/dose is within the range of 1.00±0.70 m⁻³, more preferably1.00±0.60 m⁻³, still more preferably 1.00±0.50 m⁻³, yet more preferably1.00±0.40 m⁻³, even more preferably 1.00±0.30 m⁻³, most preferably1.00±0.20 m⁻³, and in particular 1.00±0.10 m⁻³. In another preferredembodiment, the ratio C_(max)/dose is within the range of 1.10±0.70 m⁻³,more preferably 1.10±0.60 m⁻³, still more preferably 1.10±0.50 m⁻³, yetmore preferably 1.10±0.40 m⁻³, even more preferably 1.10±0.30 m⁻³, mostpreferably 1.10±0.20 m⁻³, and in particular 1.10±0.10 m⁻³. In yetanother preferred embodiment, the ratio C_(max)/dose is within the rangeof 1.20±1.05 m⁻³, more preferably 1.20±0.90 m⁻³, still more preferably1.20±0.75 m⁻³, yet more preferably 1.20±0.60 m⁻³, even more preferably1.20±0.45 m⁻³, most preferably 1.20±0.30 m⁻³, and in particular1.20±0.15 m⁻³.

In a preferred embodiment, C_(max, ≧5 days) is within the range of from1 to 150 μg/m³, more preferably within the range of from 10 to 120μg/m³, still more preferably within the range of from 15 to 100 μg/m³,yet more preferably within the range of from 20 to 80 μg/m³, mostpreferably within the range of from 20 to 70 μg/m³, and in particularwithin the range of from 25 to 60 μg/m³

In a preferred embodiment, C_(max, ≧5 days) is within the range of 25±20μg/m³, more preferably within the range of 25±15 μg/m³, still morepreferably within the range of 25±12.5 μg/m³, yet more preferably withinthe range of 25±10 μg/m³, most preferably within the range of 25±7.5μg/m³, and in particular within the range of 25±5 μg/m³. In anotherpreferred embodiment, C_(max, ≧5 days) is within the range of 30±20μg/m³, more preferably within the range of 30±15 μg/m³, still morepreferably within the range of 30±12.5 μg/m³, yet more preferably withinthe range of 30±10 μg/m³, most preferably within the range of 30±7.5μg/m³, and in particular within the range of 30±5 μg/m³. In stillanother preferred embodiment, C_(max, ≧5 days) is within the range of35±20 μg/m³, more preferably within the range of 35±15 μg/m³, still morepreferably within the range of 35±12.5 μg/m³, yet more preferably withinthe range of 35±10 μg/m³, most preferably within the range of 35±7.5μg/m³, and in particular within the range of 35±5 μg/m³. In yet anotherpreferred embodiment, C_(max, ≧5 days) is within the range of 40±20μg/m³, more preferably within the range of 40±15 μg/m³, still morepreferably within the range of 40±12.5 μg/m³, yet more preferably withinthe range of 40±10 μg/m³, most preferably within the range of 40±7.5μg/m³, and in particular within the range of 40±5 μg/m³. In a preferredembodiment, C_(max, ≧5 days) is within the range of 45±30 μg/m³, morepreferably within the range of 45±25 μg/m³, still more preferably withinthe range of 45±20 μg/m³, yet more preferably within the range of 45±15μg/m³, most preferably within the range of 45±10 μg/m³, and inparticular within the range of 45±5 μg/m³. In another preferredembodiment, C_(max, ≧5 days) is within the range of 50±30 μg/m³, morepreferably within the range of 50±25 μg/m³, still more preferably withinthe range of 50±20 μg/m³, yet more preferably within the range of 50±15μg/m³, most preferably within the range of 50±10 μg/m³, and inparticular within the range of 50±5 μg/m³. In still another preferredembodiment, C_(max, ≧5 days) is within the range of 55±30 μg/m³, morepreferably within the range of 55±25 μg/m³, still more preferably withinthe range of 55±20 μg/m³, yet more preferably within the range of 55±15μg/m³, most preferably within the range of 55±10 μg/m³, and inparticular within the range of 55±5 μg/m³. In yet another preferredembodiment, C_(max, ≧5 days) is within the range of 60±30 μg/m³, morepreferably within the range of 60±25 μg/m³, still more preferably withinthe range of 60±20 μg/m³, yet more preferably within the range of 60±15μg/m³, most preferably within the range of 60±10 μg/m³, and inparticular within the range of 60±5 μg/m³. In a preferred embodiment,C_(max, ≧5 days) is within the range of 65±30 μg/m³, more preferablywithin the range of 65±25 μg/m³, still more preferably within the rangeof 65±20 μg/m³, yet more preferably within the range of 65±15 μg/m³,most preferably within the range of 65±10 μg/m³, and in particularwithin the range of 65±5 μg/m³.

In another preferred embodiment, C_(max, ≧5 days) is within the range of70±30 μg/m³, more preferably within the range of 70±25 μg/m³, still morepreferably within the range of 70±20 μg/m³, yet more preferably withinthe range of 70±15 μg/m³, most preferably within the range of 70±10μg/m³, and in particular within the range of 70±5 μg/m³. In stillanother preferred embodiment, C_(max, ≧5 days) is within the range of75±30 μg/m³, more preferably within the range of 75±25 μg/m³, still morepreferably within the range of 75±20 μg/m³, yet more preferably withinthe range of 75±15 μg/m³, most preferably within the range of 75±10μg/m³, and in particular within the range of 75±5 μg/m³. In yet anotherpreferred embodiment, C_(max, ≧5 days) is within the range of 80±30μg/m³, more preferably within the range of 80±25 μg/m³, still morepreferably within the range of 80±20 μg/m³, yet more preferably withinthe range of 80±15 μg/m³, most preferably within the range of 80±10μg/m³, and in particular within the range of 80±5 μg/m³. In a preferredembodiment, C_(max, ≧5 days) is within the range of 85±50 μg/m³, morepreferably within the range of 85±40 μg/m³, still more preferably withinthe range of 85±30 μg/m³, yet more preferably within the range of 85±20μg/m³, most preferably within the range of 85±10 μg/m³, and inparticular within the range of 85±5 μg/m³. In another preferredembodiment, C_(max, ≧5 days) is within the range of 90±50 μg/m³, morepreferably within the range of 90±40 μg/m³, still more preferably withinthe range of 90±30 μg/m³, yet more preferably within the range of 90±20μg/m³, most preferably within the range of 90±10 μg/m³, and inparticular within the range of 90±5 μg/m³. In still another preferredembodiment, C_(max, ≧5 days) is within the range of 100±50 μg/m³, morepreferably within the range of 100±40 μg/m³, still more preferablywithin the range of 100±30 μg/m³, yet more preferably within the rangeof 100±20 μg/m³, most preferably within the range of 100±10 μg/m³, andin particular within the range of 100±5 μg/m³. In yet another preferredembodiment, C_(max, ≧5 days) is within the range of 120±30 μg/m³, morepreferably within the range of 120±25 μg/m³, still more preferablywithin the range of 120±20 μg/m³, yet more preferably within the rangeof 120±15 μg/m³, most preferably within the range of 120±10 μg/m³, andin particular within the range of 120±5 μg/m³.

Preferably, the ratio C_(max, ≧5 days)/dose is within the range of from0.25 to 1.50 m⁻³, more preferably within the range of from 0.40 to 1.10m⁻³, still more preferably within the range of from 0.45 to 1.00 m⁻³,yet more preferably within the range of from 0.50 to 0.95 m⁻³, mostpreferably within the range of from 0.55 to 0.90 m⁻³, and in particularwithin the range of from 0.60 to 0.85 m⁻³.

Preferably, the ratio C_(max, ≧5 days)/C_(max, 1 day) is ≧1.00, morepreferably ≧1.00.

In a preferred embodiment, the ratio C_(max, ≧5 days)/C_(max, 1 day) is≧1.00, more preferably ≧1.10, still more preferably ≧1.20, yet morepreferably ≧1.30, most preferably ≧1.40, and in particular ≧1.50. Inanother preferred embodiment, the ratio C_(max, ≧5 days)/C_(max, 1 day)is ≧1.60, more preferably ≧1.70, still more preferably ≧1.80, yet morepreferably ≧1.90, most preferably ≧2.00, and in particular ≧2.10.

In a preferred embodiment, the ratio C_(max, ≧5 days)/C_(max, 1 day) is≦3.10, more preferably ≦3.00, still more preferably ≦2.90, yet morepreferably ≦2.80, most preferably ≦2.70, and in particular ≦2.60. Inanother preferred embodiment, the ratio C_(max, ≧5 days)/C_(max, 1 day)is ≦2.50, more preferably ≦2.40, still more preferably ≦2.30, yet morepreferably ≦2.20, most preferably ≦2.10, and in particular ≦2.00.

For the purpose of the specification, C_(0-3h) is the highest plasmaconcentration of the pharmacologically active agent reached after asingle administration of the pharmaceutical dosage form within the first3 hours after administration. Accordingly, for the purpose of thespecification, C_(0-3h, 1 day) is the highest plasma concentration ofthe pharmacologically active agent reached within the first 3 hoursafter once daily administration of the pharmaceutical dosage form on thevery first day of an administration interval, whereas C_(0-3h, 5 day) isthe highest plasma concentration of the pharmacologically active agentreached within the first 3 hours after once daily administration of thepharmaceutical dosage form on the fifths day of said administrationinterval comprising 5 consecutive days where the dosage form isadministered once daily.

In a preferred embodiment, the pharmaceutical dosage form contains thepharmacologically active agent in a quantity so thatC_(0-3h, 5d)≦C_(0-3h, 1d). In another preferred embodiment, thepharmaceutical dosage form contains the pharmacologically active agentin a quantity so that C_(0-3h, 5d)≧C_(0-3h, 1d). In a preferredembodiment, the quotient (C_(0-3h, 5d))/(C_(0-3h, 1d)) is at most 2.5 or2.4 or 2.3, more preferably at most 2.2 or 2.1 or 2.0, still morepreferably at most 1.9 or 1.8 or 1.7, yet more preferably at most 1.6 or1.5 or 1.4, most preferably at most 1.3 or 1.2 or 1.1, and in particularat most 1.0 or 0.9 or 0.8. In another preferred embodiment, the quotient(C_(0-3h, 5d)) (C_(0-3h, 1d)) is at least 0.8 or 0.9 or 1.0, morepreferably at least 1.1 or 1.2 or 1.3, still more preferably at least1.4 or 1.5 or 1.6, yet more preferably at least 1.7 or 1.8 or 1.9, mostpreferably at least 2.0 or 2.1 or 2.2, and in particular at least 2.3 or2.4 or 2.5.

In a preferred embodiment, the highest plasma concentration of thepharmacologically active agent reached on day 5 of a 5 day long periodof once daily administration of the pharmaceutical dosage form is higherthan the highest plasma concentrations reached on the first and/orsecond and/or third and/or fourth day of said period.

In a preferred embodiment, the daily mean plasma concentration of thepharmacologically active agent is steadily increased during the first 5days of at least 5 day long period of once daily administration of thepharmaceutical dosage form.

Preferably, the plasma concentration of the pharmacologically activeagent measured 10 days after single administration of the pharmaceuticaldosage form is still at least 0.5 pg/mL, more preferably at least 1.0pg/mL, still more preferably 1.25 pg/mL, yet more preferably at least1.5 pg/mL, most preferably at least 1.75 pg/mL, and in particular atleast 2.0 pg/mL.

Preferably, the plasma concentration of the pharmacologically activeagent measured 10 drug-free days after once daily administration of thepharmaceutical dosage form for at least 5 consecutive days is still atleast 0.5 pg/mL, more preferably at least 1.0 pg/mL, still morepreferably 1.25 pg/mL, yet more preferably at least 1.5 pg/mL, mostpreferably at least 1.75 pg/mL, and in particular at least 2.0 pg/mL.

According to the invention, the pharmacokinetic parameter t_(max) iswithin the range of from 0.5 to 16 h. Preferably, t_(max) is within therange of from 1 to 12 h, and in particular within the range of from 2 to10 h.

In a preferred embodiment, t_(max) is within the range of 4±3.5 h, morepreferably 4±3 h, still more preferably 4±2.5 h, yet more preferably 4±2h, even more preferably 4±1.5 h, most preferably 4±1 h, and inparticular 4±0.5 h. In another preferred embodiment, t_(max) is withinthe range of 5±3.5 h, more preferably 5±3 h, still more preferably 5±2.5h, yet more preferably 5±2 h, even more preferably 5±1.5 h, mostpreferably 5±1 h, and in particular 5±0.5 h. In still another preferredembodiment, t_(max) is within the range of 6±4 h, more preferably 6±3 h,still more preferably 6±2.5 h, yet more preferably 6±2 h, even morepreferably 6±1.5 h, most preferably 6±1 h, and in particular 6±0.5 h. Inyet another preferred embodiment, T_(max) is within the range of 8±7 h,more preferably 8±6 h, still more preferably 8±5 h, yet more preferably8±4 h, even more preferably 8±3 h, most preferably 8±2 h, and inparticular 8±1 h. In even another preferred embodiment, T_(max) iswithin the range of 12±3 h, more preferably 12±2 h, and most preferably12±1 h.

In a preferred embodiment, t_(max, ≧5 days) is within the range of from1 to 12 h, more preferably within the range of from 1.5 to 10 h, stillmore preferably within the range of from 2 to 9 h, yet more preferablywithin the range of from 2.5 to 8 h, most preferably within the range offrom 3 to 7 h, and in particular within the range of from 4 to 6 h.

In a preferred embodiment, t_(max, ≧5 days) is within the range of 4±3.5h, more preferably 4±3 h, still more preferably 4±2.5 h, yet morepreferably 4±2 h, even more preferably 4±1.5 h, most preferably 4±1 h,and in particular 4±0.5 h. In another preferred embodiment,t_(max, ≧5 days) is within the range of 5±3.5 h, more preferably 5±3 h,still more preferably 5±2.5 h, yet more preferably 5±2 h, even morepreferably 5±1.5 h, most preferably 5±1 h, and in particular 5±0.5 h. Instill another preferred embodiment, t_(max, ≧5 days) is within the rangeof 6±4 h, more preferably 6±3 h, still more preferably 6±2.5 h, yet morepreferably 6±2 h, even more preferably 6±1.5 h, most preferably 6±1 h,and in particular 6±0.5 h.

Preferably, the ratio AUC_(0-t)/dose is within the range from 0.3 to 20h/m³, more preferably within the range of from 0.4 to 18 h/m³, stillmore preferably within the range of from 0.5 to 16.5 h/m³ and mostpreferably within the range of from 0.55 to 12.5 h/m³. In a preferredembodiment, the ratio AUC_(0-t)/dose is within the range of 3±2.5 h/m³,more preferably 3±2 h/m³, still more preferably 3±1.5 h/m³, yet morepreferably 3±1 h/m³, even more preferably 3±0.75 h/m³, most preferably3±0.5 h/m³, and in particular 3±0.25 h/m³. In another preferredembodiment, the ratio AUC_(0-t)/dose is within the range of 6±5 h/m³,more preferably 6±4 h/m³, still more preferably 6±3 h/m³, yet morepreferably 6±2 h/m³, even more preferably 6±1.5 h/m³, most preferably6±1 h/m³, and in particular 6±0.5 h/m³. In still another preferredembodiment, the ratio AUC_(0-t)/dose is within the range of 7.5±7 h/m³,more preferably 7.5±6 h/m³, still more preferably 7.5±5 h/m³, yet morepreferably 7.5±4 h/m³, even more preferably 7.5±3 h/m³, most preferably7.5±2 h/m³, and in particular 7.5±1 h/m³. In yet another preferredembodiment, the ratio AUC_(0-t)/dose is within the range of 9±8 h/m³,more preferably 9±7 h/m³, still more preferably 9±5 h/m³, yet morepreferably 9±4 h/m³, even more preferably 9±3 h/m³, most preferably 9±2h/m³, and in particular 9±1 h/m³. In another preferred embodiment, theratio AUC_(0-72h)/dose is within the range of 10±7 h/m³, more preferably10±6 h/m³, still more preferably 10±5 h/m³, yet more preferably 10±4h/m³, even more preferably 10±3 h/m³, most preferably 10±2 h/m³, and inparticular 10±1 h/m³.

Preferably, the ratio AUC_(0-72h)/dose is within the range from 0.3 to20 h/m³, more preferably within the range of from 0.4 to 18 h/m³, stillmore preferably within the range of from 0.5 to 16.5 h/m³ and mostpreferably within the range of from 0.55 to 12.5 h/m³. In a preferredembodiment, the ratio AUC_(0-72h)/dose is within the range of 3±2.5h/m³, more preferably 3±2 h/m³, still more preferably 3±1.5 h/m³, yetmore preferably 3±1 h/m³, even more preferably 3±0.75 h/m³, mostpreferably 3±0.5 h/m³, and in particular 3±0.25 h/m³. In anotherpreferred embodiment, the ratio AUC_(0-72h)/dose is within the range of6±5 h/m³, more preferably 6±4 h/m³, still more preferably 6±3 h/m³, yetmore preferably 6±2 h/m³, even more preferably 6±1.5 h/m³, mostpreferably 6±1 h/m³, and in particular 6±0.5 h/m³. In still anotherpreferred embodiment, the ratio AUC_(0-72h)/dose is within the range of7.5±7 h/m³, more preferably 7.5±6 h/m³, still more preferably 7.5±5h/m³, yet more preferably 7.5±4 h/m³, even more preferably 7.5±3 h/m³,most preferably 7.5±2 h/m³, and in particular 7.5±1 h/m³. In yet anotherpreferred embodiment, the ratio AUC_(0-72h)/dose is within the range of9±8 h/m³, more preferably 9±7 h/m³, still more preferably 9±5 h/m³, yetmore preferably 9±4 h/m³, even more preferably 9±3 h/m³, most preferably9±2 h/m³, and in particular 9±1 h/m³.

In a preferred embodiment, the pharmaceutical dosage form according tothe invention is administered once daily during an administrationinterval comprising an initial phase, during which the plasmaconcentration time profile substantially changes from day to day, and asteady state phase, during which the plasma concentration time profiledoes not substantially change from day to day. In this regard, duringthe steady state phase the plasma concentration time profile may stillchange during a day, i.e. the plasma concentration measured e.g. 1 hourafter administration may substantially differ from the plasmaconcentration measured e.g. 2, 3, 4, 6, 12 or 20 hours after the sameadministration on the same day. However, during the steady state phase,the plasma concentration measured X hours after administration on day Ndoes not substantially differ from the plasma concentration measured Xhours after the following administration on the following day N+1.Preferably, the initial phase lasts 1, 2, 3, 4 or 5 consecutive daysuntil the steady state phase commences. In a preferred embodiment,during the steady state phase, the pharmaceutical dosage form providesand maintains upon administration once daily pharmacologically effectiveplasma concentrations of the pharmacologically active agent according togeneral formula (I) for at least 12 h, preferably at least 18 h, morepreferably at least 20 h, yet more preferably at least 22 h, and inparticular all 24 h of at least 1.0 pg/mL, at least 2.0 pg/mL, or atleast 3.0 pg/mL, more preferably at least 4.0 pg/mL, at least 5.0 pg/mL,or at least 6.0 pg/mL, still more preferably at least 7.0 pg/mL, atleast 8.0 pg/mL, or at least 9.0 pg/mL, yet more preferably at least 10pg/mL, at least 12.5 pg/mL, or at least 15 pg/mL, even more preferablyat least 17.5 pg/mL, at least 20 pg/mL, or at least 22.5 pg/mL, mostpreferably at least 25 pg/mL, at least 27.5 pg/mL, or at least 30 pg/mL,and in particular at least 35 pg/mL, at least 40 pg/mL, or at least 50pg/mL.

In accordance with yet another advantageous embodiment of the inventionthe dosage form according to the invention is adapted for administrationonce daily and contains the pharmacologically active agent according togeneral formula (I) in a dose of from 150 μg to 800 μg, preferably morethan 190 μg to 800 μg, i.e. the dosage form according to the inventioncontains the pharmacologically active agent according to general formula(I) in a daily dose of from 150 μg to 800 μg.

In a preferred embodiment, the dose of the pharmacologically activeagent according to general formula (I) preferably is in the range offrom 200 μg to 800 μg, preferably in the range of from 210 μg to 750 μg,more preferably in the range of from 220 μg to 700 μg, still morepreferably in the range of from 230 μg to 650 μg, yet more preferably inthe range of from 240 μg to 600 μg, and most preferably in the range offrom 250 μg to 550 μg.

In a preferred embodiment, the dose of the pharmacologically activeagent according to general formula (I) is in the range of from 200 μg to600 μg. In a preferred embodiment, the dose of the pharmacologicallyactive agent according to general formula (I) is in the range of from300 μg to 500 μg.

In a preferred embodiment, the content of the pharmacologically activeagent according to general formula (I) in the pharmaceutical dosage formis within the range of 200±50 μg, more preferably 200±40 μg, mostpreferably 200±30 μg, and in particular 200±20 μg. In another preferredembodiment, the content of the pharmacologically active agent accordingto general formula (I) in the pharmaceutical dosage form is within therange of 250±100 μg, more preferably 250±80 μg, most preferably 250±60μg, and in particular 250±50 μg. In another preferred embodiment, thecontent of the pharmacologically active agent according to generalformula (I) in the pharmaceutical dosage form is within the range of300±150 μg, more preferably 300±125 μg, most preferably 300±100 μg, andin particular 300±50 μg. In another preferred embodiment, the content ofthe pharmacologically active agent according to general formula (I) inthe pharmaceutical dosage form is within the range of 350±200 μg, morepreferably 350±175 μg, still more preferably 350±150 μg, most preferably350±100 μg, and in particular 350±50 μg. In a preferred embodiment, thecontent of the pharmacologically active agent according to generalformula (I) in the pharmaceutical dosage form is within the range of400±250 μg, more preferably 400±225 μg, still more preferably 400±200μg, yet more preferably 400±150 μg, most preferably 400±100 μg, and inparticular 400±50 μg. In another preferred embodiment, the content ofthe pharmacologically active agent according to general formula (I) inthe pharmaceutical dosage form is within the range of 450±300 μg, morepreferably 450±275 μg, still more preferably 450±250 μg, yet morepreferably 450±200 μg, even more preferably 450±150 μg, most preferably450±100 μg, and in particular 450±50 μg. In still another preferredembodiment, the content of the pharmacologically active agent accordingto general formula (I) in the pharmaceutical dosage form is within therange of 500±350 μg, more preferably 500±300 μg, still more preferably500±250 μg, yet more preferably 500±200 μg, even more preferably 500±150μg, most preferably 500±100 μg, and in particular 500±50 μg. In yetanother preferred embodiment, the content of the pharmacologicallyactive agent according to general formula (I) in the pharmaceuticaldosage form is within the range of 550±350 μg, more preferably 550±300μg, still more preferably 550±250 μg, yet more preferably 550±200 μg,even more preferably 550±150 μg, most preferably 550±100 μg, and inparticular 550±50 μg. In a preferred embodiment, the content of thepharmacologically active agent according to general formula (I) in thepharmaceutical dosage form is within the range of 600±400 μg or 600±350μg, more preferably 600±300 μg, still more preferably 600±250 μg, yetmore preferably 600±200 μg, even more preferably 600±150 μg, mostpreferably 600±100 μg, and in particular 600±50 μg.

In a preferred embodiment, the pharmaceutical dosage form according tothe invention is adapted for oral administration. Suitable alternativepathways of administration of the pharmaceutical dosage form accordingto the invention include but are not limited to vaginal and rectaladministration.

The pharmaceutical dosage form according to the invention is intendedfor administration once daily.

For the purpose of the specification, “administration once daily” (sid,OD) preferably means that the pharmaceutical dosage form is adapted forbeing administered according to a regimen comprising the administrationof a first pharmaceutical dosage form according to the invention and thesubsequent administration of a second pharmaceutical dosage formaccording to the invention, wherein both, the first and the secondpharmaceutical dosage form are administered during a time interval ofabout 48 hours, but wherein the second pharmaceutical dosage form isadministered not earlier than 18 hours, preferably not earlier than 20hours, more preferably not earlier than 22 hours and in particular,about 24 hours after the first pharmaceutical dosage form has beenadministered.

A skilled person is fully aware that administration regimens “oncedaily” may be realized by administering a single pharmaceutical dosageform containing the full amount of the pharmacologically active agentaccording to general formula (I) to be administered at a particularpoint in time or, alternatively, administering a multitude of doseunits, i.e. two, three or more dose units, the sum of which multitude ofdose units containing the full amount of the pharmacologically activeagent according to general formula (I) to be administered at saidparticular point in time, where the individual dose units are adaptedfor simultaneous administration or administration within a short periodof time, e.g. within 5, 10 or 15 minutes.

The dosage form according to the invention is for use in the treatmentof nociceptive pain, preferably acute or chronic nociceptive pain.Preferably, the pain is moderate, severe, or moderate to severe.

Nociceptive pain refers to the discomfort that results when a stimuluscauses tissue damage to the muscles, bones, skin or internal organs. Forthe purpose of the specification, nociceptive pain is caused bystimulation of peripheral nerve fibers that respond only to stimuliapproaching or exceeding harmful intensity (nociceptors), and may beclassified according to the mode of noxious stimulation; the most commoncategories being “thermal” (heat or cold), “mechanical” (crushing,tearing, etc.) and “chemical” (iodine in a cut, chili powder in theeyes). Nociceptive pain may also be divided into “visceral,” “deepsomatic” and “superficial somatic” pain.

Visceral pain describes a type of nociceptive pain originating in thebody's internal organs or their surrounding tissues. This form of painusually results from the infiltration of harmful cells, as well as thecompression or extension of healthy cells. Patients suffering fromvisceral pain tend to feel generally achy, as this pain tends to not belocalized to a specific area. Cancer is a common source of visceralpain.

Somatic pain is nociceptive pain that results from some injury to thebody. It's generally localized to the affected area and abates when thebody repairs the damage to that area. Deep somatic pain is initiated bystimulation of nociceptors in ligaments, tendons, bones, blood vessels,fasciae and muscles, and is dull, aching, poorly-localized pain.Examples include sprains and broken bones. Superficial pain is initiatedby activation of nociceptors in the skin or superficial tissues, and issharp, well-defined and clearly located.

According to the invention, nociceptive pain is preferably classifiedchronic if it has occurred for at least 3 months. Preferably, thechronic nociceptive pain is selected from chronic visceral pain, chronicdeep somatic pain and chronic superficial somatic pain.

Preferred causes of nociceptive pain according to the invention includebroken or fractured bones, bruises, burns, cuts, inflammation (frominfection or arthritis), and sprains. Thus, nociceptive pain includespost-operative pain, cancer pain, low back pain, and inflammatory pain.

In another preferred embodiment, the pain to be treated is selected fromthe group consisting of pain being or being associated with panicdisorder [episodic paroxysmal anxiety] [F41.0]; dissociative[conversion] disorders [F44]; persistent somatoform pain disorder[F45.4]; pain disorders exclusively related to psychological factors[F45.41]; nonorganic dyspareunia [F52.6]; other enduring personalitychanges [F62.8]; sadomasochism [F65.5]; elaboration of physical symptomsfor psychological reasons [F68.0]; migraine [G43]; other headachesyndromes [G44]; trigeminal neuralgia [G50.0]; atypical facial pain[G50.1]; phantom limb syndrome with pain [G54.6]; phantom limb syndromewithout pain [G54.7]; acute and chronic pain, not elsewhere classified[G89]; ocular pain [H57.1]; otalgia [H92.0]; angina pectoris,unspecified [120.9]; other specified disorders of nose and nasal sinuses[J34.8]; other diseases of pharynx [J39.2]; temporomandibular jointdisorders [K07.6]; other specified disorders of teeth and supportingstructures [K08.8]; other specified diseases of jaws [K10.8]; other andunspecified lesions of oral mucosa [K13.7]; glossodynia [K14.6]; otherspecified diseases of anus and rectum [K62.8]; pain in joint [M25.5];shoulder pain [M25.51]; sacrococcygeal disorders, not elsewhereclassified [M53.3]; spine pain [M54.]; radiculopathy [M54.1];cervicalgia [M54.2]; sciatica [M54.3]; low back pain [M54.5]; pain inthoracic spine [M54.6]; other dorsalgia [M54.8]; dorsalgia, unspecified[M54.9]; other shoulder lesions [M75.8]; other soft tissue disorders,not elsewhere classified [M79]; myalgia [M79.1]; neuralgia and neuritis,unspecified [M79.2]; pain in limb [M79.6]; other specified disorders ofbone [M89.8]; unspecified renal colic [N23]; other specified disordersof penis [N48.8]; other specified disorders of male genital organs[N50.8]; mastodynia [N64.4]; pain and other conditions associated withfemale genital organs and menstrual cycle [N94]; mittelschmerz [N94.0];other specified conditions associated with female genital organs andmenstrual cycle [N94.8]; pain in throat and chest [R07]; pain in throat[R07.0]; chest pain on breathing [R07.1]; precordial pain [R07.2]; otherchest pain [R07.3]; chest pain, unspecified [R07.4]; abdominal andpelvic pain [R10]; acute abdomen pain [R10.0]; pain localized to upperabdomen [R10.1]; pelvic and perineal pain [R10.2]; pain localized toother parts of lower abdomen [R10.3]; other and unspecified abdominalpain [R10.4]; flatulence and related conditions [R14]; abdominalrigidity [R19.3]; other and unspecified disturbances of skin sensation[R20.8]; pain associated with micturition [R30]; other and unspecifiedsymptoms and signs involving the urinary system [R39.8]; headache [R51];pain, not elsewhere classified [R52]; acute pain [R52.0]; chronicintractable pain [R52.1]; other chronic pain [R52.2]; pain, unspecified[R52.9]; other complications of cardiac and vascular prosthetic devices,implants and grafts [T82.8]; other complications of genitourinaryprosthetic devices, implants and grafts [T83.8]; other complications ofinternal orthopaedic prosthetic devices, implants and grafts [T84.8];other complications of internal prosthetic devices, implants and grafts,not elsewhere classified [T85.8]; wherein the information in bracketsrefers to the classification according to ICD-10. The invention alsorelates to a pharmacologically active agent according to general formula(I) or a physiologically acceptable salt thereof for use in thetreatment of pain, preferably neuropathic pain as described above,preferably by means of administering once daily the pharmaceuticaldosage form according to the invention.

In accordance with yet another preferred embodiment of the invention,C_(max) is preferably within the range of from 1 to 250 μg/m³, morepreferably within the range of from 10 to 220 μg/m³, still morepreferably within the range of from 40 to 200 μg/m³, most preferablywithin the range of from 60 to 170 μg/m³, and in particular within therange of from 80 to 150 μg/m³.

In a preferred embodiment, C_(max) is within the range of 90±80 μg/m³,more preferably within the range of 90±70 μg/m³, still more preferablywithin the range of 90±60 μg/m³, yet more preferably within the range of90±50 μg/m³, even more preferably within the range of 90±40 μg/m³, mostpreferably within the range of 90±30 μg/m³, and in particular within therange of 90±20 μg/m³. In another preferred embodiment, C_(max) is withinthe range of 100±80 μg/m³, more preferably within the range of 100±70μg/m³, still more preferably within the range of 100±60 μg/m³, yet morepreferably within the range of 100±50 μg/m³, even more preferably withinthe range of 100±40 μg/m³, most preferably within the range of 100±30μg/m³, and in particular within the range of 100±20 μg/m³. In stillanother preferred embodiment, C_(max) is within the range of 110±80μg/m³, more preferably within the range of 110±70 μg/m³, still morepreferably within the range of 110±60 μg/m³, yet more preferably withinthe range of 110±50 μg/m³, even more preferably within the range of110±40 μg/m³, most preferably within the range of 110±30 μg/m³, and inparticular within the range of 110±20 μg/m³. In yet another preferredembodiment, C_(max) is within the range of 120±80 μg/m³, more preferablywithin the range of 120±70 μg/m³, still more preferably within the rangeof 120±60 μg/m³, yet more preferably within the range of 120±50 μg/m³,even more preferably within the range of 120±40 μg/m³, most preferablywithin the range of 120±30 μg/m³, and in particular within the range of120±20 μg/m³. In a preferred embodiment, C_(max) is within the range of130±80 μg/m³, more preferably within the range of 130±70 μg/m³, stillmore preferably within the range of 130±60 μg/m³, yet more preferablywithin the range of 130±50 μg/m³, even more preferably within the rangeof 130±40 μg/m³, most preferably within the range of 130±30 μg/m³, andin particular within the range of 130±20 μg/m³. In another preferredembodiment, C_(max) is within the range of 140±80 μg/m³, more preferablywithin the range of 140±70 μg/m³, still more preferably within the rangeof 140±60 μg/m³, yet more preferably within the range of 140±50 μg/m³,even more preferably within the range of 140±40 μg/m³, most preferablywithin the range of 140±30 μg/m³, and in particular within the range of140±20 μg/m³. In still another preferred embodiment, C_(max) is withinthe range of 150±80 μg/m³, more preferably within the range of 150±70μg/m³, still more preferably within the range of 150±60 μg/m³, yet morepreferably within the range of 150±50 μg/m³, even more preferably withinthe range of 150±40 μg/m³, most preferably within the range of 150±30μg/m³, and in particular within the range of 150±20 μg/m³. In yetanother preferred embodiment, C_(max) is within the range of 160±80μg/m³, more preferably within the range of 160±70 μg/m³, still morepreferably within the range of 160±60 μg/m³, yet more preferably withinthe range of 160±50 μg/m³, even more preferably within the range of160±40 μg/m³, most preferably within the range of 160±30 μg/m³, and inparticular within the range of 160±20 μg/m³. In a preferred embodiment,C_(max) is within the range of 170±80 μg/m³, more preferably within therange of 170±70 μg/m³, still more preferably within the range of 170±60μg/m³, yet more preferably within the range of 170±50 μg/m³, even morepreferably within the range of 170±40 μg/m³, most preferably within therange of 170±30 μg/m³, and in particular within the range of 170±20μg/m³.

Preferably, the ratio C_(max)/dose is within the range of from 0.01 to3.00 m⁻³, yet more preferably within the range of from 0.02 to 2.50 m⁻³,more preferably within the range of from 0.04 to 2.00 m⁻³, and mostpreferably within the range of from 0.06 to 1.69 m⁻³.

In a preferred embodiment, the ratio C_(max)/dose is within the range of0.25±0.20 m⁻³, more preferably 0.25±0.15 m⁻³, still more preferably0.25±0.10 m⁻³, and most preferably 0.25±0.15 m⁻³. In a preferredembodiment, the ratio C_(max)/dose is within the range of 0.30±0.25 m⁻³,more preferably 0.30±0.20 m⁻³, still more preferably 0.30±0.15 m⁻³, mostpreferably 0.30±0.10 m⁻³, and in particular 0.30±0.05 m⁻³. In anotherpreferred embodiment, the ratio C_(max)/dose is within the range of0.40±0.35 m⁻³, more preferably 0.40±0.30 m⁻³, still more preferably0.40±0.25 m⁻³, yet more preferably 0.40±0.20 m⁻³, even more preferably0.40±0.15 m⁻³, most preferably 0.40±0.10 m⁻³, and in particular0.40±0.05 m⁻³. In still another preferred embodiment, the ratioC_(max)/dose is within the range of 0.50±0.35 m⁻³, more preferably0.50±0.30 m⁻³, still more preferably 0.50±0.25 m⁻³, yet more preferably0.50±0.20 m⁻³, even more preferably 0.50±0.15 m⁻³, most preferably0.50±0.10 m⁻³, and in particular 0.50±0.05 m⁻³. In yet another preferredembodiment, the ratio C_(max)/dose is within the range of 0.60±0.40 m⁻³,more preferably 0.60±0.30 m⁻³, still more preferably 0.60±0.25 m⁻³, yetmore preferably 0.60±0.20 m⁻³, most preferably 0.60±0.15 m⁻³, and inparticular 0.60±0.10 m⁻³. In even another preferred embodiment, theratio C_(max)/dose is within the range of 0.70±0.40 m⁻³, more preferably0.70±0.35 m⁻³, still more preferably 0.70±0.30 m⁻³, yet more preferably0.70±0.25 m⁻³, even more preferably 0.70±0.20 m⁻³, most preferably0.70±0.15 m⁻³, and in particular 0.70±0.10 m⁻³. In a preferredembodiment, the ratio C_(max)/dose is within the range of 0.80±0.70 m⁻³,more preferably 0.80±0.60 m⁻³, still more preferably 0.80±0.50 m⁻³, yetmore preferably 0.80±0.40 m⁻³, even more preferably 0.80±0.30 m⁻³, mostpreferably 0.80±0.20 m⁻³, and in particular 0.80±0.10 m⁻³. In anotherpreferred embodiment, the ratio C_(max)/dose is within the range of0.90±0.70 m⁻³, more preferably 0.90±0.60 m⁻³, still more preferably0.90±0.50 m⁻³, yet more preferably 0.90±0.40 m⁻³, even more preferably0.90±0.30 m⁻³, most preferably 0.90±0.20 m⁻³, and in particular0.90±0.10 m⁻³. In still another preferred embodiment, the ratioC_(max)/dose is within the range of 1.00±0.70 m⁻³, more preferably1.00±0.60 m⁻³, still more preferably 1.00±0.50 m⁻³, yet more preferably1.00±0.40 m⁻³, even more preferably 1.00±0.30 m⁻³, most preferably1.00±0.20 m⁻³, and in particular 1.00±0.10 m⁻³. In another preferredembodiment, the ratio C_(max)/dose is within the range of 1.10±0.70 m⁻³,more preferably 1.10±0.60 m⁻³, still more preferably 1.10±0.50 m⁻³, yetmore preferably 1.10±0.40 m⁻³, even more preferably 1.10±0.30 m⁻³, mostpreferably 1.10±0.20 m⁻³, and in particular 1.10±0.10 m⁻³. In yetanother preferred embodiment, the ratio C_(max)/dose is within the rangeof 1.20±1.05 m⁻³, more preferably 1.20±0.90 m⁻³, still more preferably1.20±0.75 m⁻³, yet more preferably 1.20±0.60 m⁻³, even more preferably1.20±0.45 m⁻³, most preferably 1.20±0.30 m⁻³, and in particular1.20±0.15 m⁻³.

In a preferred embodiment, the highest plasma concentration of thepharmacologically active agent reached on day 5 of a 5 day long periodof once daily administration of the pharmaceutical dosage form is higherthan the highest plasma concentrations reached on the first and/orsecond and/or third and/or fourth day of said period.

In a preferred embodiment, the daily mean plasma concentration of thepharmacologically active agent is steadily increased during the first 5days of at least 5 day long period of once daily administration of thepharmaceutical dosage form.

Preferably, the plasma concentration of the pharmacologically activeagent measured 10 days after single administration of the pharmaceuticaldosage form is still at least 0.5 μg/mL, more preferably at least 1.0pg/mL, still more preferably 1.25 pg/mL, yet more preferably at least1.5 pg/mL, most preferably at least 1.75 pg/mL, and in particular atleast 2.0 pg/mL.

Preferably, the plasma concentration of the pharmacologically activeagent measured 10 drug-free days after once daily administration of thepharmaceutical dosage form for at least 5 consecutive days is still atleast 0.5 pg/mL, more preferably at least 1.0 pg/mL, still morepreferably 1.25 pg/mL, yet more preferably at least 1.5 pg/mL, mostpreferably at least 1.75 pg/mL, and in particular at least 2.0 pg/mL.

According to the invention, the pharmacokinetic parameter t_(max) iswithin the range of from 0.5 to 16 h. Preferably, t_(max) is within therange of from 1 to 12 h, and in particular within the range of from 2 to10 h.

In a preferred embodiment, T_(max) is within the range of 4±3.5 h, morepreferably 4±3 h, still more preferably 4±2.5 h, yet more preferably 4±2h, even more preferably 4±1.5 h, most preferably 4±1 h, and inparticular 4±0.5 h. In another preferred embodiment, T_(max) is withinthe range of 5±3.5 h, more preferably 5±3 h, still more preferably 5±2.5h, yet more preferably 5±2 h, even more preferably 5±1.5 h, mostpreferably 5±1 h, and in particular 5±0.5 h. In still another preferredembodiment, t_(max) is within the range of 6±4 h, more preferably 6±3 h,still more preferably 6±2.5 h, yet more preferably 6±2 h, even morepreferably 6±1.5 h, most preferably 6±1 h, and in particular 6±0.5 h. Inyet another preferred embodiment, t_(max) is within the range of 7±6 h,more preferably 7±5 h, still more preferably 7±4 h, yet more preferably7±3 h, even more preferably 7±2 h, most preferably 7±1 h, and inparticular 7±0.5 h. In yet another preferred embodiment, T_(max) iswithin the range of 8±7 h, more preferably 8±6 h, still more preferably8±5 h, yet more preferably 8±4 h, even more preferably 8±3 h, mostpreferably 8±2 h, and in particular 8±1 h. In even another preferredembodiment, t_(max) is within the range of 12±3 h, more preferably 12±2h, and most preferably 12±1 h.

Preferably, the ratio AUC_(0-t)/dose is within the range from 0.3 to 20h/m³, more preferably within the range of from 0.4 to 18 h/m³, stillmore preferably within the range of from 0.5 to 16.5 h/m³ and mostpreferably within the range of from 0.55 to 12.5 h/m³. In a preferredembodiment, the ratio AUC_(0-t)/dose is within the range of 3±2.5 h/m³,more preferably 3±2 h/m³, still more preferably 3±1.5 h/m³, yet morepreferably 3±1 h/m³, even more preferably 3±0.75 h/m³, most preferably3±0.5 h/m³, and in particular 3±0.25 h/m³. In another preferredembodiment, the ratio AUC_(0-t)/dose is within the range of 6±5 h/m³,more preferably 6±4 h/m³, still more preferably 6±3 h/m³, yet morepreferably 6±2 h/m³, even more preferably 6±1.5 h/m³, most preferably6±1 h/m³, and in particular 6±0.5 h/m³. In still another preferredembodiment, the ratio AUC_(0-t)/dose is within the range of 7.5±7 h/m³,more preferably 7.5±6 h/m³, still more preferably 7.5±5 h/m³, yet morepreferably 7.5±4 h/m³, even more preferably 7.5±3 h/m³, most preferably7.5±2 h/m³, and in particular 7.5±1 h/m³. In yet another preferredembodiment, the ratio AUC_(0-t)/dose is within the range of 9±8 h/m³,more preferably 9±7 h/m³, still more preferably 9±5 h/m³, yet morepreferably 9±4 h/m³, even more preferably 9±3 h/m³, most preferably 9±2h/m³, and in particular 9±1 h/m³. In another preferred embodiment, theratio AUC_(0-72h)/dose is within the range of 10±7 h/m³, more preferably10±6 h/m³, still more preferably 10±5 h/m³, yet more preferably 10±4h/m³, even more preferably 10±3 h/m³, most preferably 10±2 h/m³, and inparticular 10±1 h/m³.

In a preferred embodiment, AUC_(0-t) is within the range of 3750±3500h·pg/mL, more preferably 3750±3000 h·pg/mL, still more preferably3750±2500 h·pg/mL, yet more preferably 3750±2000 h·pg/mL, even morepreferably 3750±1500 h·pg/mL, most preferably 3750±1000 h·pg/mL, and inparticular 3750±500 h·pg/mL.

Preferably, the ratio AUC_(0-72h)/dose is within the range from 0.3 to20 h/m³, more preferably within the range of from 0.4 to 18 h/m³, stillmore preferably within the range of from 0.5 to 16.5 h/m³ and mostpreferably within the range of from 0.55 to 12.5 h/m³. In a preferredembodiment, the ratio AUC_(0-72h)/dose is within the range of 3±2.5h/m³, more preferably 3±2 h/m³, still more preferably 3±1.5 h/m³, yetmore preferably 3±1 h/m³, even more preferably 3±0.75 h/m³, mostpreferably 3±0.5 h/m³, and in particular 3±0.25 h/m³. In anotherpreferred embodiment, the ratio AUC_(0-72h)/dose is within the range of6±5 h/m³, more preferably 6±4 h/m³, still more preferably 6±3 h/m³, yetmore preferably 6±2 h/m³, even more preferably 6±1.5 h/m³, mostpreferably 6±1 h/m³, and in particular 6±0.5 h/m³. In still anotherpreferred embodiment, the ratio AUC_(0-72h)/dose is within the range of7.5±7 h/m³, more preferably 7.5±6 h/m³, still more preferably 7.5±5h/m³, yet more preferably 7.5±4 h/m³, even more preferably 7.5±3 h/m³,most preferably 7.5±2 h/m³, and in particular 7.5±1 h/m³. In yet anotherpreferred embodiment, the ratio AUC_(0-72h)/dose is within the range of9±8 h/m³, more preferably 9±7 h/m³, still more preferably 9±5 h/m³, yetmore preferably 9±4 h/m³, even more preferably 9±3 h/m³, most preferably9±2 h/m³, and in particular 9±1 h/m³.

In a preferred embodiment, AUC₀₋₇₂ is within the range of 2800±2500h·pg/mL, more preferably 2800±2250 h·pg/mL, still more preferably2800±2000 h·pg/mL, yet more preferably 2800±1750 h·pg/mL, even morepreferably 2800±1500 h·pg/mL, most preferably 2800±1000 h·pg/mL, and inparticular 2800±500 h·pg/mL.

In a preferred embodiment, the pharmaceutical dosage form according tothe invention is administered once daily during an administrationinterval comprising an initial phase, during which the plasmaconcentration time profile substantially changes from day to day, and asteady state phase, during which the plasma concentration time profiledoes not substantially change from day to day. In this regard, duringthe steady state phase the plasma concentration time profile may stillchange during a day, i.e. the plasma concentration measured e.g. 1 hourafter administration may substantially differ from the plasmaconcentration measured e.g. 2, 3, 4, 6, 12 or 20 hours after the sameadministration on the same day. However, during the steady state phase,the plasma concentration measured X hours after administration on day Ndoes not substantially differ from the plasma concentration measured Xhours after the following administration on the following day N+1.Preferably, the initial phase lasts 1, 2, 3, 4 or 5 consecutive daysuntil the steady state phase commences. In a preferred embodiment,during the steady state phase, the pharmaceutical dosage form providesand maintains upon administration once daily pharmacologically effectiveplasma concentrations of the pharmacologically active agent according togeneral formula (I) for at least 12 h, preferably at least 18 h, morepreferably at least 20 h, yet more preferably at least 22 h and inparticular all 24 h of at least 25 pg/mL, at least 30 pg/mL, or at least35 pg/mL, more preferably at least 40 pg/mL, at least 45 pg/mL, or atleast 50 pg/mL, still more preferably at least 60 pg/mL, at least 70pg/mL, or at least 80 pg/mL, yet more preferably at least 90 pg/mL, atleast 100 pg/mL, or at least 110 pg/mL, even more preferably at least120 pg/mL, at least 130 pg/mL, or at least 140 pg/mL, most preferably atleast 150 pg/mL, at least 160 pg/mL, or at least 170 pg/mL, and inparticular at least 180 pg/mL, at least 190 pg/mL, or at least 200pg/mL. In another preferred embodiment, during the steady state phase,the ratio of the maximum plasma concentration C_(max) to the plasmaconcentration measured 3 h after administration C_(3h), i.e.C_(max)/C_(3h), is not more than 3.9, not more than 3.8, or not morethan not more than 3.7, preferably not more than 3.6, not more than 3.5,or not more than not more than 3.4, more preferably not more than 3.3,not more than 3.2, or not more than not more than 3.1, still morepreferably not more than 3.0, not more than 2.9, or not more than notmore than 2.8, yet more preferably not more than 2.7, not more than 2.6,or not more than not more than 2.5, even more preferably not more than2.4, not more than 2.3, or not more than not more than 2.2, mostpreferably not more than 2.1, not more than 2.0, or not more than notmore than 1.9, and in particular preferably not more than 1.8, not morethan 1.7, or not more than not more than 1.6.

In a preferred embodiment, the pharmaceutical dosage form according tothe invention is monolithic.

In another preferred embodiment, the pharmaceutical dosage formaccording to the invention comprises a core that is surrounded by acoating or by an encapsulating material. In a preferred embodiment, thecore is liquid and the pharmacologically active agent according togeneral formula (I) is dispersed, preferably dissolved in the liquid.

In another preferred embodiment the pharmaceutical dosage form accordingto the invention provides the pharmacologically active agent accordingto general formula (I) in form of self-(micro) emulsifying drug deliverysystems, solid solutions, nanoparticles, cyclodextrin complexes,liposomes, micelles, micronized and/or amorphous states.

In general terms, the options for formulation of poorly water-solubledrugs include crystalline solid, amorphous and lipid formulations.

The dissolution rate of the pharmacologically active agent fromcrystalline formulations can be increased by particle size reduction,thereby increasing the surface area for dissolution, e.g. byconventional micronisation of the pharmacologically active agent toparticle sizes of about 2-5 μm. In some cases, this is not sufficientand nanocrystal technology is applied. Nanocrystals show a particle sizeof 100-250 nm, which can be obtained by ball-milling or by dense gas orsupercritical fluid technology.

Solid solutions provide and sustain the pharmacologically active agentin an amorphous or semi-amorphous state immobilized in a polymer.Amorphous solutions may contain surfactants and polymers, therebyproviding surface-activity during dispersion upon contact with water.Solid solutions can be formed using a variety of technologies such asspray drying and melt extrusion.

Lipid formulations exhibiting different characteristics can be used todisperse and form micellar solutions, including simple solutions andself-emulsifying drug delivery systems (SEDDS). Depending on theexcipients, some require digestion (e.g. simple oily liquids), otherscan easily be absorbed without digestion. Lipid formulations have beenclassified according to the lipid formulation classification system(LFCS) as follows:

Content of formulation (wt.-%) Excipients Type Type Type Type Type informulation I II IIIA IIIB IV Oil: triglycerides 100 40-80 40-80 <20 —or mixed mono- and diglycerides Water-insoluble — 20-60 — — 0-20surfactants (HLB < 12) Water-soluble surfactants — — 20-40 20-50 30-80 (HLB > 12) Hydrophilic co-solvent — —  0-40 20-50 0-50

Another option is the formation of cyclodextrin complexes, in which thepharmacologically active agent is located in the cavity of thecyclodextrin and is thereby molecularly present in a more soluble formin presence of aqueous media. The success of the fitting stronglydepends on the quality of the cyclodextrins as well as on thephysicochemical properties and size of the pharmacologically activeagent.

In a preferred embodiment, the pharmaceutical dosage form according tothe invention can be regarded as a self emulsifying drug delivery system(SEDDS).

For that purpose, the pharmacologically active agent according togeneral formula (I) is preferably embedded in a self-emulsifyingformulation. A so called self emulsifying drug delivery system (SEDDS)is a drug delivery system that uses an emulsion achieved by chemicalrather than mechanical means. That is, by an intrinsic property of thedrug formulation, rather than by special mixing and handling. Saidformulation dilutes in aqueous media and results in an emulsion. In casethat the average droplet size is smaller than or equal to 50 nm, theself emulsifying drug delivery system (SEDDS) is referred to asself-micro emulsifying drug delivery system (SMEDDS). According to thelipid formulation classification system, these formulations aretypically assigned to the group of type III formulations.

A preferred sub-group of SEDDSs are self-emulsifying oily formulations(SEOF). SEOFs typically comprise a natural or synthetic oil, surfactantand hydrophilic solvent and sometimes co-solvents. The principalcharacteristic of SEOFs is their ability to form fine oil-in-wateremulsions or micro emulsions upon mild agitation following dilution byaqueous phases. These formulations can disperse in the gastrointestinallumen to form micro emulsions or fine emulsions, upon dilution withgastrointestinal fluids.

In another preferred embodiment, the pharmaceutical dosage form containsthe pharmacologically active agent according to general formula (I) inform of a solid solution, i.e. molecularly dispersed in a solid matrix,so that preferably the pharmaceutical dosage form as such has anamorphous or semi-amorphous nature. The solid solution preferablycomprises the pharmacologically active agent according to generalformula (I) in a molecular disperse form and an amorphous polymer matrixhaving a comparatively large specific surface. The pharmacologicallyactive agent according to general formula (I) is preferably present in amolecular disperse form, i.e. the compound is truly solved and evenlyspread in the solidified solution. The particle size of the compound isneither microcrystalline nor fine crystalline. The typical particle sizeis preferably from 0.1-1 μm.

In still another preferred embodiment, the pharmacologically activeagent according to general formula (I) is provided by means of ananotechnological formulation with an average size of the nanoparticlesof preferably less than 1 μm. The pharmacologically active agentaccording to general formula (I) is preferably blended with thenanoparticles and thus adsorbed to the surface of the nanoparticles. Thenanoparticles are preferably selected from organic nanoparticles andinorganic nanoparticles.

Organic nanoparticles preferably contain small proteins which arepresent as a cluster or an agglomerate of small proteins, oligopeptidesor lipids.

Inorganic nanoparticles preferably contain crystalline silicates. Thesesilicates are from mineral origin or artificial silicates likemetallosilicates (e.g. zeolites). In a preferred embodiment, thenanoparticles are modified in a way that they bear an electrostaticcharge. The nanoparticles are preferably ultra finely grounded silicatesand the pharmacologically active agent according to general formula (I)is preferably bounded to the micro porous surface of the nanoparticles.

The formation of nanoparticles is known to a person skilled in the art.One method is to produce colloidal nanoparticles as carriers for oraldrug release by spraying the pharmacologically active agent according togeneral formula (I) under pressure at a defined temperature, togetherwith a suitable carrier material like protamine, through jets, which areequipped with perforated strainers, into strongly cooled towers. Theresult of the fast cooling is an amorphous phase consisting ofnanoparticles. Another method is to blend the pharmacologically activeagent according to general formula (I) with suitable macromolecules insolution. By adding hydrophobic compounds, solvent molecules are removedfrom the solution and desolvation occurs. For this reason the formationof very tiny particles takes place wherein the pharmacologically activeagent according to general formula (I) is integrated. For a hardening ofthe formed nanoparticles a crosslinker may be added to the solution.

To produce for example a solid lipid nanoparticle the method ofhigh-pressure-homogenization and subsequent spray-cooling can be used.Preferably, the pharmacologically active agent according to generalformula (I) is dissolved in a suitable solvent or in form of sub-microparticles. If applicable, a lipid vehicle and a surfactant may be addedto the solution. Finally fine filler materials as outer phase as well asglidants and further surfactants may be added to fill the obtainedformulation into e.g. capsules such as hard gelatin capsules.

In yet another preferred embodiment, the pharmacologically active agentaccording to general formula (I) are provided as cyclodextrin(inclusion) complexes.

Cyclodextrins are composed of sugar molecules forming a ring andtypically comprising 5 or more α-D-glycopyranoside units which arelinked via the 1-4 position. The typical number of connected sugarmonomers ranges from 6 to 8 units. A six membered sugar ring molecule iscalled α-cyclodextrin. A seven membered sugar ring molecule is calledβ-cyclodextrin and an eight membered sugar ring molecule is calledγ-cyclodextrin. The shape of these compounds is a toroid with the largerand the smaller openings exposed to the solvent. Due to this formationthe inner part of the toroid is not hydrophobic, but considerably lesshydrophilic than the aqueous environment and thus able to hosthydrophobic molecules. The outer part of the toroid is sufficientlyhydrophilic to render cyclodextrins water solubility.

The inclusion of the pharmacologically active ingredient according togeneral formula (I) in cyclodextrins greatly modifies the physical andchemical properties. In most cases the mechanism of controlleddegradation of such complexes and resultant drug release is based on pHchange of aqueous solutions, leading to the cleavage of hydrogen orionic bonds between the cyclodextrins and the included molecules.Alternative means for the disruption of the complexes take advantage ofheating or action of enzymes able to cleave α-1-4 linkages betweenα-D-glycopyranosides.

In another preferred embodiment, the pharmacologically active agentaccording to general formula (I) is provided in form of liposomes. Aliposome is preferably composed of phospholipids and is preferably ofspherical shape. The shell of this shape is preferably a lamellar orbilayer structure. Another type of phospholipids arrangement is amonolayer.

Phospholipids comprise molecules with an amphiphilic character i.e. themolecules have a hydrophobic (lipophilic) and a hydrophilic (Iipophobic)part. In the presence of water, the hydrophilic part is attracted to thewater and forms a surface facing to the water, while the hydrophobicpart is repelled by the water and forms a surface away from the water.Hence the amphiphilic molecules arrange themselves in one of thementioned types.

The bilayer structures preferably arrange in a spherical shape whereinthe inner part is filled with an aqueous solution. This type is called“liposome”. The hydrophobic parts of the molecules face each other inthe middle of the layer and the hydrophilic parts of the molecules facethe water molecules outside of the liposome. The aqueous solution insidethe liposome is the same as it is outside of the liposome. Ingredientssolved in this aqueous solution, e.g. the pharmacologically activeagents according to general formula (I), are in this way inside of theliposome. A typical diameter of the liposomes is between 25 nm and 1 μm.The smaller ones (25 nm-200 nm) are made of one single bilayer while thebigger ones (200 nm-1 μm) comprise more bilayer shells on the top ofeach other.

The monolayer structures also arrange in spherical shapes. Due to theamphiphilic character of the molecules and the spherical shape of themonolayer structures, the inner part of the spherical structures isfilled with/formed by the hydrophobic parts of the molecules. Thesetypes are called micelles. There is no solvent inside the structure. Ina preferred embodiment, the inner parts of the micelles contain thepharmacologically active agents according to general formula (I).

In another preferred embodiment the pharmacologically active agentaccording to general formula (I) is provided in a micronized state. Bymeans of micronization technique particles of the pharmacologicallyactive agent according to general formula (I) with a diameter innanometer scale can be prepared. Said particles have a large surface tovolume ratio.

Milling and grinding is a useful method to obtain particles in nanometerscale. Sophisticated techniques for the micronization include RESS(rapid expansion of supercritical solutions), SAS (supercritical antisolvent) and the PGSS (particles from gas saturated solutions).

The RESS method uses a supercritical fluid wherein the pharmacologicallyactive agent according to general formula (I) is dissolved under highpressure and temperature thereby yielding a homogenous supercriticalphase. After expanding the solution through a nozzle, small particlesare formed. Due to the expansion at the end of the nozzle the solvedpharmacologically active agent according to general formula (I)precipitates as crystals and encloses small amounts of the solvent. Thesolvent changes from the supercritical fluid state to the normal state,preferred the gas phase, and breaks the crystals from inside-out. Inthis way and due to the fact that the crystals collide with each other,particles with a diameter in nanometer scale are formed.

In the SAS method the pharmacologically active agent according togeneral formula (I) is dissolved in a preferably organic solvent. Asupercritical fluid is added to the solution under pressure and thusforced to also dissolve in the solvent. In consequence, the volume ofthe complete system is increased and the solubility of thepharmacologically active agent according to general formula (I) isdecreased. Due to its decreased solubility, the compound according togeneral formula (I) precipitates and forms particles having a smalldiameter.

The PGSS method is similar to the SAS method. Here, thepharmacologically active agent according to general formula (I) ismelted and a supercritical fluid is dissolved in the melt. Due to theexpansion through a nozzle, the pharmacologically active agent accordingto general formula (I) precipitates and forms particles in a nanometerscale.

In a preferred embodiment, the pharmaceutical dosage form according tothe invention contains

-   -   a non-ionic surfactant (e.g. Cremophor® EL, Cremophor® RH 40,        Cremophor® RH 60, d-alpha-tocopherol polyethylene glycol 1000        succinate, polysorbate 20, polysorbate 80, Solutol® HS 15,        sorbitan monooleate, poloxamer 407, Labrafil® M-1944CS,        Labrafil® M-2125CS, Labrasol®, Gelucire® 44/14, Softigen® 767,        and mono- and di-fatty acid esters of PEG 300, 400 or 1750);        and/or    -   an anionic surfactant (e.g., Konakion® MM, Cernevit® sodium        lauryl sulfate (sodium dodecyl sulfate, e.g. Texapon® K12),        sodium cetyl sulfate (e.g. Lanette E®), sodium cetylstearyl        sulfate, sodium stearyl sulfate, sodium dioctylsulfosuccinate        (docusate sodium); and/or    -   a water insoluble lipid (e.g. castor oil, corn oil cottonseed        oil, olive oil, peanut oil, peppermint oil, safflower oil,        sesame oil, soybean oil, hydrogenated vegetable oils,        hydrogenated soybean oil, and medium chain triglycerides of        coconut oil and palm seed oil); and/or    -   an organic liquid/semi-solid (e.g. beeswax, d-alpha-tocopherol,        oleic acid, medium chain mono- and diglycerides); and/or    -   a cyclodextrin (e.g. alpha-cyclodextrin, beta-cyclodextrin,        hydroxypropyl-beta-cyclodextrin, and        sulfobutylether-beta-cyclodextrin); and/or    -   a phospholipid (e.g. hydrogenated soy phosphatidylcholine,        distearoylphosphatidyl-glycerol,        L-alpha-dimyristoylphosphatidylcholine, and        L-alpha-dimyristoylphosphatidyl-glycerol).

Preferably, the pharmacologically active agent according to generalformula (I) is molecularly dispersed in a matrix.

In a preferred embodiment, the pharmacologically active agent accordingto general formula (I) is molecularly dispersed in a non-crystallinematrix.

In another preferred embodiment, the pharmacologically active agentaccording to general formula (I) is molecularly dispersed in anon-amorphous matrix.

Preferably, the pharmacologically active agent according to generalformula (I) is homogeneously distributed in the pharmaceutical dosageform according to the invention. The content of the pharmacologicallyactive agent according to general formula (I) of two segments of thepharmaceutical dosage form having a volume of 1.0 mm³ each, deviate fromone another by preferably not more than ±10%, more preferably not morethan more than ±7.5%, still more preferably not more than ±5.0%, mostpreferably not more than ±2.5%, and in particular not more than ±1.0%.When the pharmaceutical dosage form is encapsulated or film-coated, saidtwo segments of the pharmaceutical dosage form having a volume of 1.0mm³ each are preferably segments of the core, i.e. do not contain anyencapsulating medium or film coating, respectively.

Preferably, the pharmaceutical dosage form according to the invention ischaracterized by a comparatively homogeneous distribution of density.Preferably, the densities of two segments of the pharmaceutical dosageform having a volume of 1.0 mm³ each, deviate from one another by notmore than ±10%, more preferably not more than more than ±7.5%, stillmore preferably not more than ±5.0%, most preferably not more than±2.5%, and in particular not more than ±1.0%. When the pharmaceuticaldosage form is encapsulated, said two segments of the pharmaceuticaldosage form having a volume of 1.0 mm³ each are preferably segments ofthe core, i.e. do not contain any encapsulating medium or film coating.

In a preferred embodiment, the pharmaceutical dosage form furthercontains a surfactant.

For the purpose of the specification, the term “surfactant” refers toany compound that contains at least one hydrophobic group and at leastone hydrophilic group. Preferably, the surfactant contains at least oneterminal hydrophobic group (tail) and at least one terminal hydrophilicgroup (head).

The hydrophobic group is preferably selected from the group consistingof hydrocarbon, alkyl ether, fluorocarbon and siloxan groups.

In a preferred embodiment, the surfactant contains at least onealiphatic group comprising at least 3 carbon atoms, more preferably atleast 4 carbon atoms, still more preferably at least 6 carbon atoms, yetmore preferably 6 to 30 carbon atoms, and most preferably 8 to 24 carbonatoms. The aliphatic group may be a saturated or unsaturated, branchedor unbranched (linear), terminal or internal aliphatic group.

Preferably, the surfactant contains at least one group derivable from asaturated or unsaturated fatty acid or from a saturated or unsaturatedfatty alcohol, which group is preferably an ether, carboxylic acid esteror sulfuric acid ester group. Preferably, the saturated or unsaturatedfatty acid or fatty alcohol contains at least 6 carbon atoms, yet morepreferably 6 to 30 carbon atoms, and most preferably 8 to 24 carbonatoms.

In a preferred embodiment, the surfactant contains at least one groupderivable from a saturated or unsaturated fatty acid, preferably C₆ toC₃₀ fatty acid, more preferably C₈ to C₂₄ fatty acid, and mostpreferably C₁₂ to C₂₂ fatty acid. Examples for suitable fatty acids arelauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid,behenic acid, lignoceric acid, 12-hydroxystearic acid, oleic acid andricinoleic acid.

In another preferred embodiment, the surfactant contains at least onegroup derivable from a saturated or unsaturated fatty alcohol,preferably C₆ to C₃₀ fatty alcohol, more preferably C₈ to C₂₄ fattyalcohol, and most preferably C₁₂ to C₂₂ fatty alcohol. Examples forsuitable fatty alcohols are cetyl alcohol, stearyl alcohol,2-octyldodecane-1-ol and 2-hexyldecane-1-ol.

Preferably, the surfactant has a molecular weight of at most 20,000g/mol, more preferably at most 15,000 g/mol, still more preferably atmost 10,000 g/mol, yet more preferably at most 5,000 g/mol, even morepreferably at most 4,000 g/mol, most preferably at most 3,000 g/mol, andin particular within the range of from 100 g/mol to 2,500 g/mol.

Preferably, the surfactant is contained in a matrix in which thepharmacologically active agent according to general formula (I) isdispersed, preferably molecularly.

In a preferred embodiment, the pharmacologically active agent accordingto general formula (I) and the surfactant are intimately homogeneouslydistributed in a matrix so that the matrix does not contain any segmentswhere either the pharmacologically active agent according to generalformula (I) is present in the absence of the surfactant or where thesurfactant is present in the absence of the pharmacologically activeagent according to general formula (I).

In a preferred embodiment, the pharmaceutical dosage form contains asurfactant. In another preferred embodiment, the pharmaceutical dosageform contains a mixture of two or more surfactants.

In a preferred embodiment, the surfactant acts as an oil-in-water (O/W)emulsifier. In another preferred embodiment, the surfactant acts as awater-in-oil (W/O) emulsifier.

Preferably, the pharmaceutical dosage form contains a surfactant havinga hydrophilic-lipophilic balance (HLB) of at least 10 or at least 11.More preferably, the hydrophilic-lipophilic balance (HLB) is at least 12or at least 13. Most preferably, the hydrophilic-lipophilic balance(HLB) ranges within 14 and 16.

Preferably, the hydrophilic-lipophilic balance (HLB) of the surfactantis at most 30, more preferably at most 28, still more preferably at most26, yet more preferably at most 24, even more preferably at most 22,most preferably at most 20 and in particular at most 18.

In another preferred embodiment, the hydrophilic-lipophilic balance(HLB) of the surfactant is at least 27, more preferably at least 29,still more preferably at least 31, yet more preferably at least 33, evenmore preferably at least 35, most preferably at least 37 and inparticular at least 39. An especially preferred surfactant of this typeis sodium lauryl sulfave having an HLB value of about 40.

In a preferred embodiment, the HLB value of the surfactant is within therange of 10±3.5, more preferably 10±3, still more preferably 10±2.5, yetmore preferably 10±2, even more preferably 10±1.5, most preferably 10±1,and in particular 10±0.5. In another preferred embodiment, the HLB valueof the surfactant is within the range of 12±3.5, more preferably 12±3,still more preferably 12±2.5, yet more preferably 12±2, even morepreferably 12±1.5, most preferably 12±1, and in particular 12±0.5. Instill another preferred embodiment, the HLB value of the surfactant iswithin the range of 14±3.5, more preferably 14±3, still more preferably14±2.5, yet more preferably 14±2, even more preferably 14±1.5, mostpreferably 14±1, and in particular 14±0.5. In another preferredembodiment, the HLB value of the surfactant is within the range of15±3.5, more preferably 15±3, still more preferably 15±2.5, yet morepreferably 15±2, even more preferably 15±1.5, most preferably 15±1, andin particular 15±0.5. In yet another preferred embodiment, the HLB valueof the surfactant is within the range of 16±3.5, more preferably 16±3,still more preferably 16±2.5, yet more preferably 16±2, even morepreferably 16±1.5, most preferably 16±1, and in particular 16±0.5. Inanother preferred embodiment, the HLB value of the surfactant is withinthe range of 18±3.5, more preferably 18±3, still more preferably 18±2.5,yet more preferably 18±2, even more preferably 18±1.5, most preferably18±1, and in particular 18±0.5.

In another preferred embodiment, the HLB value of the surfactant iswithin the range of 30±3.5, more preferably 30±3, still more preferably30±2.5, yet more preferably 30±2, even more preferably 30±1.5, mostpreferably 30±1, and in particular 30±0.5. In another preferredembodiment, the HLB value of the surfactant is within the range of32±3.5, more preferably 32±3, still more preferably 32±2.5, yet morepreferably 32±2, even more preferably 32±1.5, most preferably 32±1, andin particular 32±0.5. In still another preferred embodiment, the HLBvalue of the surfactant is within the range of 34±3.5, more preferably34±3, still more preferably 34±2.5, yet more preferably 34±2, even morepreferably 34±1.5, most preferably 34±1, and in particular 34±0.5. Inanother preferred embodiment, the HLB value of the surfactant is withinthe range of 36±3.5, more preferably 36±3, still more preferably 36±2.5,yet more preferably 36±2, even more preferably 36±1.5, most preferably36±1, and in particular 36±0.5. In yet another preferred embodiment, theHLB value of the surfactant is within the range of 38±3.5, morepreferably 38±3, still more preferably 38±2.5, yet more preferably 38±2,even more preferably 38±1.5, most preferably 38±1, and in particular38±0.5.

In another preferred embodiment, the HLB value of the surfactant iswithin the range of 40±3.5, more preferably 40±3, still more preferably40±2.5, yet more preferably 40±2, even more preferably 40±1.5, mostpreferably 40±1, and in particular 40±0.5.

The surfactant can be ionic, amphoteric or non-ionic.

Suitable amphoteric surfactants include phospholipids, in particularlecithins such as soya bean lecithins.

In a preferred embodiment, the pharmaceutical dosage form contains anionic surfactant, in particular an anionic surfactant.

Suitable anionic surfactants include but are not limited to sulfuricacid esters such as sodium lauryl sulfate (sodium dodecyl sulfate, e.g.Texapon® K12), sodium cetyl sulfate (e.g. Lanette E®), sodiumcetylstearyl sulfate, sodium stearyl sulfate, sodiumdioctylsulfosuccinate (docusate sodium), di-[2-ethylhexyl]-succinate;and the corresponding potassium or calcium salts thereof.

Preferably, the anionic surfactant has the general formula (II-a)

C_(n)H_(2n+1)O—SO₃ ⁻M⁺  (II-a),

-   -   wherein n is an integer of from 8 to 30, preferably 10 to 24,        more preferably 12 to 18;    -   and M is selected from Li⁺, Na⁺, K⁺, NH₄ ⁺½Mg²⁺ and ½Ca²⁺.

Further suitable anionic surfactants include salts of cholic acidincluding sodium glycocholate (e.g. Konakion® MM, Cernevit®), sodiumtaurocholate and the corresponding potassium or ammonium salts.

In another preferred embodiment, the pharmaceutical dosage form containsa non-ionic surfactant. Suitable non-ionic surfactants include but arenot limited to

-   -   fatty alcohols that may be linear or branched, such as        cetylalcohol, stearylalcohol, cetylstearyl alcohol,        2-octyldodecane-1-ol and 2-hexyldecane-1-ol;    -   sterols, such as cholesterole;    -   partial fatty acid esters of sorbitan such as        sorbitanmonolaurate, sorbitanmonopalmitate,        sorbitanmonostearate, sorbitantristearate, sorbitanmonooleate,        sorbitansesquioleate and sorbitantrioleate;    -   partial fatty acid esters of polyoxyethylene sorbitan        (polyoxyethylene-sorbitan-fatty acid esters), preferably a fatty        acid monoester of polyoxyethylene sorbitan, a fatty acid diester        of polyoxyethylene sorbitan, or a fatty acid triester of        polyoxyethylene sorbitan; e.g. mono- and tri-lauryl, palmityl,        stearyl and oleyl esters, such as the type known under the name        “polysorbat” and commercially available under the trade name        “Tween” including Tween® 20 [polyoxyethylene(20)sorbitan        monolaurate], Tween® 21 [polyoxyethylene(4)sorbitan        monolaurate], Tween® 40 [polyoxyethylene(20)sorbitan        monopalmitate], Tween® 60 [polyoxyethylene(20)sorbitan        monostearate], Tween® 65 [polyoxyethylene(20)sorbitan        tristearate], Tween® 80 [polyoxyethylene(20)sorbitan        monooleate], Tween 81 [polyoxyethylene(5)sorbitan monooleate],        and Tween® 85 [polyoxyethylene(20)sorbitan trioleate];        preferably a fatty acid monoester of polyoxyethylenesorbitan        according to general formula (II-b)

-   -   -   wherein (w+x+y+z) is within the range of from 15 to 100,            preferably 16 to 80, more preferably 17 to 60, still more            preferably 18 to 40 and most preferably 19 to 21;

    -   and alkylene is an optionally unsaturated alkylene group        comprising 6 to 30 carbon atoms, more preferably 8 to 24 carbon        atoms and most preferably 10 to 16 carbon atoms;

    -   polyoxyethyleneglycerole fatty acid esters such as mixtures of        mono-, di- and triesters of glycerol and di- and monoesters of        macrogols having molecular weights within the range of from 200        to 4000 g/mol, e.g., macrogolglycerolcaprylocaprate,        macrogolglycerollaurate, macrogolglycerolococoate,        macrogolglycerollinoleate, macrogol-20-glycerolmonostearate,        macrogol-6-glycerolcaprylocaprate, macrogolglycerololeate;        macrogolglycerolstearate, macrogolglycerolhydroxystearate (e.g.        Cremophor® RH 40), and macrogolglycerolrizinoleate (e.g.        Cremophor® EL);

    -   polyoxyethylene fatty acid esters, the fatty acid preferably        having from about 8 to about 18 carbon atoms, e.g.        macrogololeate, macrogolstearate, macrogol-15-hydroxystearate,        polyoxyethylene esters of 12-hydroxystearic acid, such as the        type known and commercially available under the trade name        “Solutol HS 15”; preferably according to general formula (II-c)

CH₃CH₂—(OCH₂CH₃)_(n)—O—CO—(CH₂)_(m)CH₃  (II-c)

-   -   -   wherein n is an integer of from 6 to 500, preferably 7 to            250, more preferably 8 to 100, still more preferably 9 to            75, yet more preferably 10 to 50, even more preferably 11 to            30, most preferably 12 to 25, and in particular 13 to 20;            and        -   wherein m is an integer of from 6 to 28; more preferably 6            to 26, still more preferably 8 to 24, yet more preferably 10            to 22, even more preferably 12 to 20, most preferably 14 to            18 and in particular 16;

    -   polyoxyethylene fatty alcohol ethers, e.g.        macrogolcetylstearylether, macrogollarylether,        macrogololeylether, macrogolstearylether;

    -   polyoxypropylene-polyoxyethylene block copolymers (poloxamers);

    -   fatty acid esters of saccharose; e.g. saccharose distearate,        saccharose dioleate, saccharose dipalmitate, saccharose        monostearate, saccharose monooleate, saccharose monopalmitate,        saccharose monomyristate and saccharose monolaurate;

    -   fatty acid esters of polyglycerol, e.g. polyglycerololeate;

    -   polyoxyethylene esters of alpha-tocopheryl succinate, e.g.        D-alpha-tocopheryl-PEG-1000 succinate (TPGS);

    -   polyglycolyzed glycerides, such as the types known and        commercially available under the trade names “Gelucire 44/14”,        “Gelucire 50/13 and “Labrasol”;

    -   reaction products of a natural or hydrogenated castor oil and        ethylene oxide such as the various liquid surfactants known and        commercially available under the trade name “Cremophor”; and

    -   partial fatty acid esters of multifunctional alcohols, such as        glycerol fatty acid esters, e.g. mono- and tri-lauryl, palmityl,        stearyl and oleyl esters, for example glycerol monostearate,        glycerol monooleate, e.g. glyceryl monooleate 40, known and        commercially available under the trade name “Peceol”; glycerole        dibehenate, glycerole distearate, glycerole monolinoleate;        ethyleneglycol monostearate, ethyleneglycol monopalmitostearate,        pentaerythritol monostearate.

In a particularly preferred embodiment, the pharmaceutical dosage formaccording to the invention comprises a surfactant or mixture ofdifferent surfactants obtainable by

-   -   (i) esterifying saturated or unsaturated C₁₂-C₁₈-fatty acids,        optionally bearing a hydroxyl group, with a polyethylene glycol        and optionally, glycerol; wherein the polyethylene glycol        preferably comprises 10 to 40 ethylene oxide units (—CH₂CH₂O—);        and/or    -   (ii) etherifying triglycerides of saturated or unsaturated        C₁₂-C₁₈-fatty acids bearing a hydroxyl group with ethylene oxide        so that a polyethylene glycol moiety is linked to the hydroxyl        group of the C₁₂-C₁₈-fatty acids via an ether bond; wherein the        polyethylene glycol moiety preferably comprises 30 to 50        ethylene oxide units (—CH₂CH₂O—).

Preferably, the surfactant is selected from the group consisting ofmacrogolhydroxystearate, macrogolglycerylhydroxystearate andmacrogolglyceryllaurate, wherein the macrogol moiety preferablycomprises 15 to 45 ethylene oxide units.

Especially preferred surfactants of this class that are contained in thepharmaceutical dosage form according to the invention are non-ionicsurfactants having a hydrophilic-lipophilic balance (HLB) of at least10, in particular non-ionic surfactants having an HLB value of at least12, more in particular non-ionic surfactant's having an HLB value within14 and 16. Examples for this type of surfactants are the above-listedsurfactants “polysorbate 80” (Tween® 80) and “Solutol® HS 15”.

Solutol® HS-15 is a mixture of polyethyleneglycol 660 12-hydroxystearateand polyethylene glycol. It is a white paste at room temperature thatbecomes liquid at about 30° C. and has an HLB of about 15.

Tween® 80 [polyoxyethylene(20)sorbitan monooleate] is liquid at roomtemperature, has a viscosity of 375-480 mPa·s and has an HLB of about15.

In another preferred embodiment the pharmaceutical dosage form accordingto the invention contains a mixture of at least one surfactant having aHLB value of at least 10 (hydrophilic surfactant) and at least onesurfactant having a HLB value below 10 (lipophilic surfactant). Forexample, the dosage form may contain macrogol-glycerolhydroxystearat 40(e.g., Cremophor® RH 40) as the hydrophilic surfactant component andglyceryl monooleate 40 (e.g., Peceol®) as the lipophilic surfactantcomponent.

Preferably, the relative weight ratio of the surfactant having a HLBvalue of at least 10 (hydrophilic surfactant) and the surfactant havinga HLB value below 10 (lipophilic surfactant) is within the range of 15:1to 1:20, more preferably 10:1 to 1:15, still more preferably 8:1 to1:12, yet more preferably 6:1 to 1:10, even more preferably 5:1 to 1:7,most preferably 4:1 to 1:4 and in particular 2:1 to 1:2.

In a preferred embodiment, the content of the surfactant is at least0.001 wt.-% or at least 0.005 wt.-%, more preferably at least 0.01 wt.-%or at least 0.05 wt.-%, still more preferably at least 0.1 wt.-%, atleast 0.2 wt.-%, or at least 0.3 wt.-%, yet more preferably at least 0.4wt.-%, at least 0.5 wt.-%, or at least 0.6 wt.-%, and in particular atleast 0.7 wt.-%, at least 0.8 wt.-%, at least 0.9 wt.-%, or at least 1.0wt.-%, based on the total weight of the pharmaceutical dosage form.

In another preferred embodiment, particularly when the pharmaceuticaldosage form contains an encapsulated core, the content of the surfactantis at least 10 wt.-%, more preferably at least 15 wt.-%, still morepreferably at least 20 wt.-%, yet more preferably at least 25 wt.-% andin particular at least 30 wt.-%, based on the total weight of thecomposition forming the core. In a preferred embodiment, the content ofthe surfactant ranges preferably from 0.1 wt.-% to 95 wt.-%, morepreferably from 1 wt.-% to 95 wt.-%, still more preferably from 5 wt.-%to 90 wt.-%, yet more preferably from 10 wt.-% to 80 wt.-%, mostpreferably from 20 wt.-% to 70 wt.-%, and in particular from 30 wt.-% to75 wt.-%, based on the total weight of the composition forming the core.

In a preferred embodiment, the pharmaceutical dosage form contains acore that is encapsulated by an encapsulating medium. The core can beliquid, semi-liquid or solid.

Preferably, said encapsulating medium is a soft gelatin capsule or ahard gelatin capsule, in particular a hard gelatin capsule.

In one preferred embodiment, the pharmaceutical dosage form comprises aliquid core encapsulated by a solid material, wherein thepharmacologically active agent according to general formula (I) isdispersed in the liquid core. Preferably, the solid material is a hardgelatin capsule.

In another preferred embodiment, the pharmaceutical dosage formaccording to the invention contains a self-emulsifying formulation inwhich the pharmacologically active agent according to general formula(I) is preferably embedded. Preferably, the pharmacologically activeagent according to general formula (I) is molecularly dispersed in theother ingredients of liquid core. For the purpose of the specification,“molecularly dispersed in a liquid core”, e.g. in the other ingredientsof the liquid core, means that a substantial portion of the overallcontent of the pharmacologically active agent according to generalformula (I) is present in non-crystalline form, i.e. does not provideX-ray reflexes. Preferably, the pharmacologically active agent accordingto general formula (I) is dissolved in the other ingredients of thecore. Preferably, the content of non-crystalline pharmacologicallyactive agent according to general formula (I) is at least 60 wt.-%, morepreferably at least 65 wt.-%, still more preferably at least 70 wt.-%,yet more preferably at least 75 wt.-%, even more preferably at least 80wt.-%, most preferably at least 85 wt.-%, and in particular at least 90wt.-%, based on the total content of pharmacologically active agentaccording to general formula (I).

In a preferred embodiment, the self-emulsifying formulation contains thesurfactant and an oil.

In another preferred embodiment, the self-emulsifying formulation is aself-emulsifying oily formulation (SEOF), i.e. it comprises thesurfactant, the oil and additionally a hydrophilic solvent.

For the purpose of the specification, an oil is preferably to beregarded as any substance that is liquid at ambient temperatures or hasa melting point below 70° C. and is hydrophobic but soluble in organicsolvents.

Preferably, the oil is a C₁₂-C₁₈-fatty acid ester of a monoalcohol (e.g.C₁-C₁₂-alkylalcohols), a di-C₁₂-C₁₈-fatty acid ester of a dialcohol(e.g. ethylene glycol) or tri-C₁₂-C₁₈-fatty acid ester of a trialcohol(e.g. glycerol).

Preferably, the oil has a melting point below 60° C., more preferablybelow 55° C., still more preferably below 50° C., yet more preferablybelow 45° C., even more preferably below 40° C., most preferably below35° C. and in particular below 30° C.

Preferably, the pure oil has a density within the range of 0.94±0.07g/cm³, more preferably 0.94±0.06 g/cm³, still more preferably 0.94±0.05g/cm³, yet more preferably 0.94±0.04 g/cm³, even more preferably0.94±0.03 g/cm³, most preferably 0.94±0.02 g/cm³, and in particular0.94±0.01 g/cm³.

Preferably, the pure oil has a viscosity at 20° C. measured inaccordance with Ph. Eur. 2.2.8, within the range of 30±9 mPas, morepreferably 30±8 mPas, still more preferably 30±7 mPas, yet morepreferably 30±6 mPas, even more preferably 30±5 mPas, most preferably30±4 mPas, and in particular 30±3 mPas.

In a preferred embodiment, the oil is selected from the group consistingof

-   -   saturated C₈ to C₁₄ fatty acids, such as myristic acid;    -   unsaturated C₈ to C₁₈ fatty acids and their esters, such as        oleic acid and ethyl oleate;    -   mixtures of saturated and unsaturated C₈ to C₁₈ fatty acids,        such as soybean oil and peanut oil; and    -   triglycerides of fatty acids, preferably of C₆ to C₁₂ fatty        acids, more preferably of C₆ to C₁₀ fatty acids, such as the        caprylic/capric triglyceride mixtures, most preferably        medium-chain triglycerides according to Ph. Eur. or USP, e.g.        known and commercially available under the trade names “Captex        355” and Miglyol 812″; and    -   propylene glycol fatty acid esters such as propylene glycol        monocaprylate (known and commercially available under the trade        names “Capryol 90”).

Especially preferred are medium-chain triglycerides according to Ph.Eur. or USP such as said caprylic/capric triglyceride mixtures.

In a preferred embodiment, the content of the oil in the pharmaceuticaldosage form is within the range of from 1 wt.-% to 90 wt.-%, preferablyfrom 2 wt.-% to 80 wt.-%, more preferably from 5 wt.-% to 60 wt.-%,still more preferably from 10 wt.-% to 50 wt.-% and most preferably from15 wt.-% to 30 wt.-%, preferably based on the total weight of the core.

In a preferred embodiment, the relative weight ratio of the surfactantto the oil is within the range of from 20:1 to 1:20, more preferably10:1 to 1:10, still more preferably 7.5:1 to 1:5, yet more preferably7:1 to 1:1, most preferably 5:1 to 1.5:1 and in particular 4:1 to 2:1.

In another preferred embodiment, particularly when the pharmaceuticaldosage form is a tablet, the content of the surfactant ranges preferablyfrom 0.001 wt.-% to 95 wt.-%, more preferably from 0.01 wt.-% to 50wt.-%, still more preferably from 0.1 wt.-% to 20 wt.-%, yet morepreferably from 0.15 wt.-% to 15 wt.-%, most preferably from 0.2 wt.-%to 10 wt.-%, and in particular from 0.25 wt.-% to 5 wt.-%, based on thetotal weight of the dosage form. In a preferred embodiment, the contentof the surfactant is at most 25 wt.-%, more preferably at most 20 wt.-%,still more preferably at most 15 wt.-%, yet more preferably at most 10wt.-% and in particular at most 5 wt.-%, based on the total weight ofthe pharmaceutical dosage form. In case that the dosage form is coated,the indication “wt.-%” preferably refers to the weight of the surfactantper total weight of the composition forming the core, i.e. thepharmaceutical dosage form without its coating.

In a preferred embodiment, the content of the surfactant is within therange of 1±0.7 wt.-%, more preferably 1±0.6 wt.-%, still more preferably1±0.5 wt.-%, yet more preferably 1±0.4 wt.-%, even more preferably 1±0.3wt.-%, most preferably 1±0.2 wt.-%, and in particular 1±0.1 wt.-%

Preferably, the self-emulsifying formulation is present as the liquidcore, encapsulated by a hard gelatin capsule.

In a preferred embodiment, the self-emulsifying formulation furthercontains a hydrophilic solvent.

Preferably, the hydrophilic solvent is an organic alcohol such as anorganic monoalcohol, organic dialcohol or organic trialcohol.

Preferably, the pure hydrophilic solvent has a boiling point at ambientpressure within the range of 78±22° C., more preferably 78±18° C., stillmore preferably 78±15° C., yet more preferably 78±12° C., even morepreferably 78±8° C., most preferably 78±5° C., and in particular 78±2°C.

Preferably, the hydrophilic solvent is selected from the group ethanol,isopropanol, glycerol and propylene glycol; especially preferred isethanol. Preferably, the content of the hydrophilic solvent is withinthe range of from about 1 wt.-% to about 90 wt.-%, preferably from about2 wt.-% to about 80 wt.-%, more preferably from about 5 wt.-% to about60 wt.-%, still more preferably from about 10 wt.-% to about 50 wt.-%,most preferably from about 15 wt.-% to about 30 wt.-%, preferably basedon the total weight of the core.

In a preferred embodiment, the pharmaceutical dosage form contains aliquid core comprising the pharmacologically active agent according togeneral formula (I), a surfactant, an oil and a hydrophilic solvent,wherein the relative weight ratio of surfactant:oil:hydrophilic solventis within the range of 60:20±17.5:20±17.5, more preferably60:20±15:20±15, still more preferably 60:20±12.5:20±12.5, yet morepreferably 60:20±10:20±10, even more preferably 60:20±7.5:20±7.5, mostpreferably 60:20±5:20±5, and in particular 60:20±2.5:20±2.5.

In another preferred embodiment, the pharmaceutical dosage form containsa liquid core comprising the pharmacologically active agent according togeneral formula (I), a surfactant having a HLB value of at least 10(hydrophilic surfactant), an oil and a surfactant having a HLB valuebelow 10 (lipophilic surfactant), wherein the relative weight ratio ofhydrophilic:oil:lipophilic solvent is within the range of60:20±17.5:20±17.5, more preferably 60:20±15:20±15, still morepreferably 60:20±12.5:20±12.5, yet more preferably 60:20±10:20±10, evenmore preferably 60:20±7.5:20±7.5, most preferably 60:20±5:20±5, and inparticular 60:20±2.5:20±2.5.

In another preferred embodiment, the pharmaceutical dosage form containsa liquid core comprising the pharmacologically active agent according togeneral formula (I), a surfactant having a HLB value of at least 10(hydrophilic surfactant), an oil and a surfactant having a HLB valuebelow 10 (lipophilic surfactant), wherein the relative weight ratio ofhydrophilic:oil:lipophilic solvent is within the range of40:40±35:20±17.5, more preferably 40:40±30:20±15, still more preferably40:40±25:20±12.5, yet more preferably 40:40±20:20±10, even morepreferably 40:40±15:20±7.5, most preferably 40:40±10:20±5, and inparticular 40:40±5:20±2.5.

Preferred embodiments A¹ to A²⁰ of the liquid core of the pharmaceuticaldosage form according to the invention, i.e. of the liquid core that isencapsulated by an encapsulating material, are summarized in thefollowing Table 1:

TABLE 1 embodiment A¹ A² A³ A⁴ ingredient nature cont. nature cont.nature cont. nature cont. pharmacologically W¹ 0.50 ± 0.49 W¹ 0.50 ±0.49 W¹ 0.50 ± 0.49 W¹ 0.50 ± 0.49 active agent according to generalformula (I) surfactant X¹ 30 ± 25 X¹ 45 ± 30 X¹ 60 ± 40 X¹ 60 ± 40 oilY¹ 40 ± 35 Y¹ 40 ± 30 Y¹ 15 ± 10 Y¹ 25 ± 20 additional component Z¹ 30 ±25 Z¹ 15 ± 10 Z¹ 25 ± 20 Z¹ 15 ± 10 embodiment A⁵ A⁶ A⁷ A⁸ ingredientnature cont. nature cont. nature cont. nature cont. pharmacologically W¹0.50 ± 0.49 W¹ 0.25 ± 0.24 W² 0.25 ± 0.24 W² 0.25 ± 0.24 active agentaccording to general formula (I) surfactant X¹ 60 ± 40 X² 40 ± 15 X² 60± 20 X² 60 ± 20 oil Y¹ 20 ± 15 Y² 30 ± 15 Y² 10 ± 5  Y² 30 ± 15additional component Z¹ 20 ± 15 Z² 30 ± 15 Z² 30 ± 15 Z² 10 ± 5 embodiment A⁹ A¹⁰ A¹¹ A¹² ingredient nature cont. nature cont. naturecont. nature cont. pharmacologically W² 0.25 ± 0.24 W² 0.25 ± 0.24 W²0.10 ± 0.09 W² 0.10 ± 0.09 active agent according to general formula (I)surfactant X² 50 ± 15 X² 60 ± 15 X³ 40 ± 10 X³ 50 ± 10 oil Y²  25 ± 7.5Y²  20 ± 7.5 Y³ 30 ± 10 Y³ 30 ± 10 additional component Z²  25 ± 7.5 Z² 20 ± 7.5 Z³ 30 ± 10 Z³  20 ± 7.5 embodiment A¹³ A¹⁴ A¹⁵ A¹⁶ ingredientnature cont. nature cont. nature cont. nature cont. pharmacologically W²0.10 ± 0.09 W³ 0.10 ± 0.09 W³ 0.10 ± 0.05  W³ 0.02 ± 0.01  active agentaccording to general formula (I) surfactant X³ 60 ± 10 X³ 70 ± 10 X⁴ 50± 5   X⁴ 50 ± 5   oil Y³ 20 ± 10 Y³ 15 ± 5  Y⁴ 25 ± 2.5 Y⁴ 25 ± 2.5additional component Z³ 20 ± 20 Z³ 15 ± 5  Z⁴ 25 ± 2.5 Z⁴ 25 ± 2.5embodiment A¹⁷ A¹⁸ A¹⁹ A²⁰ ingredient nature cont. nature cont. naturecont. nature cont. pharmacologically W³ 0.10 ± 0.05  W³ 0.02 ± 0.01  W³0.10 ± 0.05  W³ 0.02 ± 0.01  active agent according to general formula(I) surfactant X⁴ 60 ± 5   X⁴ 60 ± 5   X⁴ 60 ± 5   X⁴ 60 ± 5   oil Y⁴ 25± 2.5 Y⁴ 25 ± 2.5 Y⁴ 20 ± 2.5 Y⁴ 20 ± 2.5 additional component Z⁴ 15 ±2.5 Z⁴ 15 ± 2.5 Z⁴ 20 ± 2.5 Z⁴ 20 ± 2.5wherein

-   nature refers to the chemical nature of the ingredient;-   cont. refers to the content of the ingredient in wt.-% based on the    total weight of the core;-   W¹ means pharmacologically active agent according to general    formula (I) or a physiologically acceptable salt thereof;-   W² means pharmacologically active agent according to general formula    (I′) or a physiologically acceptable salt thereof;-   W³ means    (1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amine,    or    (1r,4r)-6′-fluoro-N-methyl-4-phenyl-4′,9′-dihydro-3′H-spiro-[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amine,    or a physiologically acceptable salt thereof;-   X¹ means surfactant having a HLB value of at least 10;-   X² means non-ionic surfactant having a HLB value of between 14 and    16;-   X³ means polyglycolyzed glyceride;-   X⁴ means polyoxyethylene fatty acid ester, the fatty acid preferably    having from about 8 to about 18 carbon atoms;-   Y¹ means mono-, di- or triester of the C₆ to C₁₈ fatty acids;-   Y² means triglycerides of C₆ to C₁₂ fatty acids (medium-chain    triglycerides);-   Y³ means propylene glycol fatty acid ester;-   Y⁴ caprylic/capric triglyceride mixture;-   Z¹ means hydrophilic solvent-   Z² means hydrophilic solvent selected from organic monoalcohol,    dialcohol or trialcohol;-   Z³ means surfactant having a HLB value of below 10;-   Z⁴ means ethanol.

For example, according to the above table, embodiment A⁹ relates to apharmaceutical dosage according to the invention, which contains apharmacologically active agent according to general formula (I′) or aphysiologically acceptable salt thereof in an amount of 0.25±0.24 wt.-%,a non-ionic surfactant having a HLB value of between 14 and 16 in anamount of 50±15 wt.-%, triglycerides of the C₆ to C₁₂ fatty acids in anamount of 25±7.5% and a hydrophilic solvent selected from organicmonoalcohol, dialcohol or trialcohol in an amount of 25±7.5%, based onthe total weight of the liquid core.

Preferably, the self-emulsifying formulation is a lipid formulation oftype IIIA or type IIIB, according to the lipid formulationclassification system (LFCS).

Preferably, the self emulsifying formulation gives emulsions with anaverage droplet size smaller than or equal to 10 micrometers, morepreferably smaller than or equal to 1000 nanometers, most preferablysmaller than or equal to 100 nanometers, when exposed to aqueous media.

In another preferred embodiment, the self-emulsifying formulation is aself-micro emulsifying drug delivery system (SMEDDS), i.e. when exposedto aqueous media, the formulation gives microemulsions with an averagedroplet size smaller than or equal to 50 nanometers, which contain thepharmacologically active agent according to general formula (I). Inanother preferred embodiment, the average droplet size is smaller thanor equal to 10 nanometers

In a preferred embodiment, the average droplet size is within the rangeof 50±70 nm, more preferably 50±60 nm, still more preferably 50±50 nm,yet more preferably 50±40 nm, even more preferably 50±30 nm, mostpreferably 50±20 nm, and in particular 50±10 nm.

In a preferred embodiment, the average droplet size is within the rangeof 75±70 nm, more preferably 75±60 nm, still more preferably 75±50 nm,yet more preferably 75±40 nm, even more preferably 75±30 nm, mostpreferably 75±20 nm, and in particular 75±10 nm.

In a preferred embodiment, the average droplet size is within the rangeof 100±70 nm, more preferably 100±60 nm, still more preferably 100±50nm, yet more preferably 100±40 nm, even more preferably 100±30 nm, mostpreferably 100±20 nm, and in particular 100±10 nm.

In a preferred embodiment, the average droplet size is within the rangeof 125±70 nm, more preferably 125±60 nm, still more preferably 125±50nm, yet more preferably 125±40 nm, even more preferably 125±30 nm, mostpreferably 125±20 nm, and in particular 125±10 nm.

In a preferred embodiment, the average droplet size is within the rangeof 150±70 nm, more preferably 150±60 nm, still more preferably 150±50nm, yet more preferably 150±40 nm, even more preferably 150±30 nm, mostpreferably 150±20 nm, and in particular 150±10 nm.

In a particular preferred embodiment,

-   -   the pharmaceutical dosage form contains a surfactant having a        HLB value of at least 10 in an amount of at least 0.001 wt.-%,        based on the total weight of the pharmaceutical dosage form;        and/or    -   the pharmaceutical dosage form contains 0.01% to 95% of the        pharmacologically active agent (A); and/or    -   the pharmaceutical dosage form has a weight within the range of        from 0.1 mg to 2,000 mg; and/or    -   the pharmaceutical dosage form contains a polymer with a        molecular weight within the range of from 1,000 g/mol to 15        million g/mol; and/or    -   the pharmaceutical dosage form is for oral administration;        and/or    -   the pharmaceutical dosage form contains the pharmacologically        active agent according to general formula (I) in a dose of from        10 μg to 50 μg or of from 300 μg to 500 μg; and/or    -   the pharmaceutical dosage form provides immediate release of the        pharmacologically active agent according to general formula (I)        in vitro in accordance with Ph. Eur.; and/or    -   the pharmaceutical dosage form, wherein the active agent        according to general formula (I) is molecularly dispersed;        and/or    -   the pharmaceutical dosage form contains a self emulsifying        formulation or a self-micro emulsifying formulation; and/or    -   the pharmaceutical dosage form comprises a liquid core        encapsulated by a solid material, wherein the pharmacologically        active agent according to general formula (I) is dispersed in        the liquid core; and/or    -   the pharmaceutical dosage form, wherein said liquid core further        contains an oil; and/or    -   the content of said oil is at least 5 wt.-%, based on the total        weight of the liquid core; and/or    -   the pharmaceutical dosage form contains a coating, preferably a        coating that is soluble in gastric juice; and/or    -   t_(max) is within the range of from 0.5 to 16 h; and/or    -   the ratio AUC_(0-t)/dose is within the range of from 0.5 to 16.5        h/m³; and/or    -   ratio C_(max)/dose is within the range of from 0.06 to 1.69 m⁻³.

In a particular preferred embodiment,

-   -   the pharmaceutical dosage form contains a surfactant having a        HLB value of at least 10 in an amount of at least 0.001 wt.-%,        based on the total weight of the pharmaceutical dosage form;        and/or    -   the pharmaceutical dosage form contains 0.01% to 95% of the        pharmacologically active agent (A); and/or    -   the pharmaceutical dosage form has a weight within the range of        from 0.1 mg to 2,000 mg; and/or    -   the pharmaceutical dosage form contains a polymer with a        molecular weight within the range of from 1,000 g/mol to 15        million g/mol; and/or    -   the pharmaceutical dosage form is for oral administration;        and/or    -   the pharmaceutical dosage form contains the pharmacologically        active agent according to general formula (I) in a dose of from        10 μg to 50 μg or of from 300 μg to 500 μg; and/or    -   the pharmaceutical dosage form provides immediate release of the        pharmacologically active agent according to general formula (I)        in vitro in accordance with Ph. Eur.; and/or    -   t_(max) is within the range of from 0.5 to 16 h; and/or    -   the ratio AUC_(0-t)/dose is within the range of from 0.5 to 16.5        h/m³; and/or    -   ratio C_(max)/dose is within the range of from 0.06 to 1.69 m⁻³.

In a preferred embodiment the pharmaceutical dosage form according tothe invention, particularly when it contains the pharmacologicallyactive agent according to general formula (I) in form of a solidsolution, i.e. molecularly dispersed in a solid matrix, may furthercontain at least one matrix material. Preferably, said matrix materialcomprises a polymer selected from the group consisting ofpolyvinylpyrrolidone, vinylpyrrolidone-polyvinylacetate copolymers,cellulose derivatives, preferably cellulose esters or cellulose ethers,such as for example hydroxypropyl methylcellulose, hydroxypropylmethylcellulose acetate succinate, hydroxy-propyl methylcellulosephthalate, ethylcellulose, polymethacrylates, polyethylene oxides,polyethylene glycols and any combinations thereof. Preferred examples ofpolyvinyl-pyrrolidone are commercialized as Kollidon® 90 and examples ofvinylpyrrolidone-polyvinyl acetate copolymer are commercialized asKollidon® VA64.

For the purpose of the specification, “molecularly dispersed in a solidmatrix”, e.g. in a polymer, means that a substantial portion of theoverall content of the pharmacologically active agent according togeneral formula (I) is present in non-crystalline form, i.e. does notprovide X-ray reflexes. Preferably, the content of non-crystallinepharmacologically active agent according to general formula (I) is atleast 60 wt.-%, more preferably at least 65 wt.-%, still more preferablyat least 70 wt.-%, yet more preferably at least 75 wt.-%, even morepreferably at least 80 wt.-%, most preferably at least 85 wt.-%, and inparticular at least 90 wt.-%, based on the total content ofpharmacologically active agent corresponding to formula (I).

In a preferred embodiment the pharmaceutical dosage form according tothe invention contains a polymer with a weight average molecular weightof preferably at least 50,000 g/mol, more preferably at least 100,000g/mol, yet more preferably at least 250,000 g/mol, still more preferablyat least 500,000 g/mol, most preferably at least 750,000 g/mol and inparticularly at least 800,000 g/mol.

In another preferred embodiment the pharmaceutical dosage form accordingto the invention contains a polymer with a weight average molecularweight of preferably at least 5000 g/mol, more preferably at least10,000 g/mol, yet more preferably at least 20,000 g/mol, still morepreferably at least 30,000 g/mol, even more preferably at least 40,000g/mol, most preferably at least 50,000 g/mol and in particular withinthe range of from 50,000 g/mol to 250,000 g/mol.

In a preferred embodiment, the pharmaceutical dosage form according tothe invention contains the pharmacologically active agent according togeneral formula (I) in form of a solid solution, i.e. molecularlydispersed in a solid matrix, wherein the matrix comprises one or morepolymers and wherein the content of the polymer(s) is within the rangeof 25±22.5 wt.-%, more preferably 25±20 wt.-%, still more preferably25±17.5 wt.-%, yet more preferably 25±15 wt.-%, even more preferably25±12.5 wt.-%, most preferably 25±10 wt.-% and in particular 25±7.5wt.-%, based on the total weight of the pharmaceutical dosage form.

In another preferred embodiment, the pharmaceutical dosage formaccording to the invention contains the pharmacologically active agentaccording to general formula (I) in form of a solid solution, i.e.molecularly dispersed in a solid matrix, wherein the matrix comprisesone or more polymers and wherein the content of the polymer(s) is withinthe range of 50±22.5 wt.-%, more preferably 50±20 wt.-%, still morepreferably 50±17.5 wt.-%, yet more preferably 50±15 wt.-%, even morepreferably 50±12.5 wt.-%, most preferably 50±10 wt.-% and in particular50±7.5 wt.-%, based on the total weight of the pharmaceutical dosageform.

In still another preferred embodiment, the pharmaceutical dosage formaccording to the invention contains the pharmacologically active agentaccording to general formula (I) in form of a solid solution, i.e.molecularly dispersed in a solid matrix, wherein the matrix comprisesone or more polymers and wherein the content of the polymer(s) is withinthe range of 75±22.5 wt.-%, more preferably 75±20 wt.-%, still morepreferably 75±17.5 wt-%, yet more preferably 75±15 wt.-%, even morepreferably 75±12.5 wt.-%, most preferably 75±10 wt.-% and in particular75±7.5 wt.-%, based on the total weight of the pharmaceutical dosageform.

In a preferred embodiment, the pharmaceutical dosage form according tothe invention contains a polymer which comprises repeating units derivedfrom vinylpyrrolidones. In another preferred embodiment the polymercomprises monomer units derived from vinyl acetates. Preferably, thepolymer is a copolymer comprising repeating units derived fromvinylpyrrolidones and repeating units derived from vinyl acetates,wherein the weight ratio of repeating units derived fromvinylpyrrolidones:repeating units derived from vinyl acetates ispreferably at most 10:1, more preferably at most 4.5:1, still morepreferably at most 4:1, most preferably at most 2:1 and in particular atmost 1.5:1.

In a preferred embodiment, the relative weight ratio of the polymerrelated to the pharmacologically active agent according to generalformula (I) in the pharmaceutical dosage form according to the inventionranges from 1:1 to 70:1, more preferably from 2:1 to 50:1, still morepreferably from 3:1 to 40:1, most preferably from 3.5:1 to 30:1 and inparticular from 4:1 to 19:1. Preferably, the relative weight ratio ofthe polymer related to the pharmacologically active agent according togeneral formula (I) in the pharmaceutical dosage form according to theinvention is at least 3:1 or at least 4:1, more preferably at least 5:1or at least 6:1, still more preferably at least 7:1 or at least 8:1, yetmore preferably at least 9:1 or at least 10:1, even more preferably atleast 11:1 or at least 12:1, most preferably at least 13:1 or at least14:1 and in particular at least 15:1 or at least 16:1.

In a preferred embodiment the relative weight ratio of the polymer,especially of polyvinyl-pyrrolidone, related to the pharmacologicallyactive agent according to general formula (I) in the pharmaceuticaldosage form according to the invention ranges from 1:1 to 70:1, morepreferably from 2:1 to 45:1, still more preferably from 3:1 to 20:1,most preferably from 3.5:1 to 10:1 and in particular from 4:1 to 5:1.

In another preferred embodiment the relative weight ratio of thepolymer, especially of vinylpyrrolidone-vinyl acetate copolymer, relatedto the pharmacologically active agent according to general formula (I)in the pharmaceutical dosage form according to the invention ranges from1:1 to 70:1, more preferably from 2:1 to 55:1, still more preferablyfrom 4:1 to 40:1, most preferably from 10:1 to 25:1 and in particularfrom 15:1 to 25:1.

In a preferred embodiment the pharmaceutical dosage form according tothe invention, particularly when it contains the pharmacologicallyactive agent according to general formula (I) in form of a solidsolution, i.e. molecularly dispersed in a solid matrix, may furthercontain at least one surfactant selected from the group containingpartial fatty acid esters of polyoxyethylene sorbitan(polyoxyethylene-sorbitan-fatty acid esters), preferably a fatty acidmonoester of polyoxyethylene sorbitan, a fatty acid diester ofpolyoxyethylene sorbitan, or a fatty acid triester of polyoxyethylenesorbitan; sulfuric acid esters, or the alkali or earthalkali saltsthereof; and poloxamers.

In a preferred embodiment the pharmaceutical dosage form according tothe invention contains a surfactant with a weight average molecularweight of preferably at least 500 g/mol, more preferably at least 1,000g/mol, yet more preferably at least 2,500 g/mol, still more preferablyat least 5,000 g/mol, most preferably at least 7,000 g/mol and inparticularly at least 8,000 g/mol.

In another preferred embodiment the pharmaceutical dosage form accordingto the invention contains a surfactant with a weight average molecularweight of preferably at least 100 g/mol, more preferably at least 250g/mol, yet more preferably at least 500 g/mol, still more preferably atleast 750 g/mol, most preferably at least 1,000 g/mol and inparticularly at least 1,250 g/mol.

In another preferred embodiment the dosage form according to theinvention contains a surfactant, preferably [polyoxyethylene(20)sorbitanmonooleate] or polyoxyethylene-polyoxypropylene block co-polymer, in acontent of preferably 0.5 wt-% to 80 wt-%, more preferably 1.5 wt-% to60 wt-%, still more preferably 2.5 wt-% to 50 wt-%, yet more preferably3.0 wt-% to 40 wt-%, most preferably 3.5 wt-% to 20 wt-%, and inparticular 4 wt-% to 10 wt-%, based on the total weight of thepharmaceutical dosage form.

Preferred embodiment A¹ to A²⁰ of the pharmaceutical dosage formaccording to the invention are summarized in the following Table 2:

TABLE 2 embodiment A¹ A² A³ A⁴ A⁵ ingredient nature ratio nature rationature Ratio nature ratio nature ratio pharmacologically X¹ 1 X¹ 1 X² 1X² 1 X³ 1 active agent according to general formula (I) polymer Y¹ 19 ±17 Y¹ 19 ± 11 Y² 19 ± 7 Y² 19 ± 5 Y³ 19 ± 3   surfactant Z¹ 5 ± 4 Z¹ 5 ±3 Z²  5 ± 2 Z²  5 ± 1 Z³ 5 ± 0.5 embodiment A⁶ A⁷ A⁸ A⁹ A¹⁰ ingredientnature ratio nature ratio nature Ratio nature ratio nature ratiopharmacologically X¹ 2 X¹ 2 X² 2 X² 2 X³ 2 active agent according togeneral formula (I) polymer Y¹ 38 ± 34 Y¹ 38 ± 22 Y² 38 ± 14 Y² 38 ± 10Y³ 38 ± 6   surfactant Z¹ 5 ± 4 Z¹ 5 ± 3 Z² 5 ± 2 Z² 5 ± 1 Z³ 5 ± 0.5embodiment A¹¹ A¹² A¹³ A¹⁴ A¹⁵ ingredient nature ratio nature rationature ratio nature ratio nature ratio pharmacologically X¹ 3 X¹ 3 X² 3X² 3 X³ 3 active agent according to general formula (I) polymer Y¹ 57 ±51 Y¹ 57 ± 33 Y² 57 ± 21 Y² 57 ± 15 Y³ 57 ± 9   surfactant Z¹ 5 ± 4 Z¹ 5± 3 Z² 5 ± 2 Z² 5 ± 1 Z³ 5 ± 0.5 embodiment A¹⁶ A¹⁷ A¹⁸ A¹⁹ A²⁰ingredient nature ratio nature ratio nature ratio nature ratio natureratio pharmacologically X¹ 4 X¹ 4 X² 4 X² 4 X³ 4 active agent accordingto general formula (I) polymer Y¹ 76 ± 68 Y¹ 76 ± 44 Y² 76 ± 28 Y² 76 ±20 Y³ 76 ± 12 surfactant Z¹ 5 ± 4 Z¹ 5 ± 3 Z² 5 ± 2 Z² 5 ± 1 Z³   5 ±0.5wherein

-   nature refers to the chemical nature of the ingredient;-   ratio refers to the relative weight proportion of the ingredient    with respect to the other two ingredients;-   X¹ means the pharmacologically active agent according to general    formula (I) or a physiologically acceptable salt thereof;-   X² means the pharmacologically active agent according to general    formula (I′) or a physiologically acceptable salt thereof;-   X³ means    (1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amine,    or    (1r,4r)-6′-fluoro-N-methyl-4-phenyl-4′,9′-dihydro-3′H-spiro-[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amine,    or a physiologically acceptable salt thereof;-   Y¹ means a polymer selected from the group consisting of    polyvinylpyrrolidone, vinylpyrrolidone-vinylacetate copolymers,    cellulose derivatives, preferably cellulose esters or cellulose    ethers, polymethacrylates, polyethylene oxides, polyethylene glycols    and any combinations thereof;-   Y² means vinylpyrrolidone-vinylacetate copolymer;-   Y³ means vinylpyrrolidone-vinylacetate copolymers having a weight    average molecular weight within the range of from 40,000 to 250,000    g/mol;-   Z¹ means a nonionic surfactan with a HLB value of 10-20;-   Z² means a surfactant selected from the group of partial fatty acid    esters of polyoxyethylene sorbitan;-   Z³ means a surfactant according to general forumla (II-b).

For example, according to the above foregoing Table 2, embodiment A⁹relates to a pharmacologically active agent according to general formula(I′) or a physiologically acceptable salt thereof, avinylpyrrolidone-polyvinylacetate copolymer and a surfactant selectedfrom the group of polysorbitanes, wherein the weight ratio is 2:38:5.

In a preferred embodiment, the content of the surfactant is within therange of 1.00±0.70 wt.-%, more preferably 1.00±0.60 wt.-%, still morepreferably 1.00±0.50 wt.-%, yet more preferably 1.00±0.40 wt.-%, evenmore preferably 1.00±0.30 wt.-%, most preferably 1.00±0.20 wt.-%, and inparticular 1.00±0.10 wt.-%

Preferred embodiments A¹ to A²⁰ of the pharmaceutical dosage formaccording to the invention are summarized in the following Table 3:

TABLE 3 embodiment A¹ A² A³ A⁴ Ingredient nature content nature contentnature content nature content pharmacologically Y¹ 0.04 ± 0.035 Y¹ 0.04± 0.025 Y² 0.04 ± 0.02 Y³ 0.04 ± 0.01 active agent according to generalformula (I) Surfactant Z¹ 2.75 ± 2.50  Z² 1.00 ± 0.50  Z³ 1.00 ± 0.20 Z⁴1.00 ± 0.10 embodiment A⁵ A⁶ A⁷ A⁸ Ingredient nature content naturecontent nature content nature content pharmacologically Y¹ 0.32 ± 0.30Y¹ 0.32 ± 0.25 Y² 0.32 ± 0.20 Y³ 0.32 ± 0.10 active agent according togeneral formula (I) Surfactant Z¹ 2.75 ± 2.50 Z² 1.00 ± 0.50 Z³ 1.00 ±0.20 Z⁴ 1.00 ± 0.10 embodiment A⁹ A¹⁰ A¹¹ A¹² Ingredient nature contentnature content nature content nature content pharmacologically Y¹ 0.50 ±0.45 Y¹ 0.50 ± 0.30 Y² 0.50 ± 0.20 Y³ 0.50 ± 0.10 active agent accordingto general formula (I) surfactant Z¹ 2.75 ± 2.50 Z² 1.00 ± 0.50 Z³ 1.00± 0.20 Z⁴ 1.00 ± 0.10 embodiment A¹³ A¹⁴ A¹⁵ A¹⁶ ingredient naturecontent nature content nature content nature content pharmacologicallyY¹ 0.60 ± 0.55 Y¹ 0.60 ± 0.40 Y² 0.60 ± 0.20 Y³ 0.60 ± 0.10 active agentaccording to general formula (I) surfactant Z¹ 2.75 ± 2.50 Z² 1.00 ±0.50 Z³ 1.00 ± 0.20 Z⁴ 1.00 ± 0.10wherein

-   nature refers to the chemical nature of the ingredient;-   content refers to the content of the ingredient in wt.-% based on    the total weight of the dosage form;-   Y¹ means pharmacologically active agent according to general    formula (I) or a physiologically acceptable salt thereof;-   Y² means pharmacologically active agent according to general formula    (I′) or a physiologically acceptable salt thereof;-   Y³ means    (1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amine,    or    (1r,4r)-6′-fluoro-N-methyl-4-phenyl-4′,9′-dihydro-3′H-spiro-[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amine,    or a physiologically acceptable salt thereof;-   Z¹ means surfactant having a HLB value of at least 10;-   Z² means anionic surfactant having a HLB value of at least 30;-   Z³ means anionic surfactant selected from the group consisting of    sodium lauryl sulfate (sodium dodecyl sulfate, e.g. Texapon® K12),    sodium cetyl sulfate (e.g. Lanette E®), sodium cetylstearyl sulfate,    sodium stearyl sulfate, sodium dioctylsulfosuccinate (docusate    sodium), di-[2-ethylhexyl]-succinate; and the corresponding    potassium or calcium salts thereof;-   Z⁴ means sodium lauryl sulfate.

For example, according to the foregoing Table 3, embodiment A⁹ relatesto a pharmaceutical dosage according to the invention, which containsthe pharmacologically active agent according to general formula (I) inan amount of 0.50±0.45 wt.-% and a surfactant having a HLB value of atleast 10 in an amount of 2.75±2.50 wt.-%, based on the total weight ofthe dosage form.

In a particular preferred embodiment,

-   -   the pharmaceutical dosage form contains a surfactant having a        HLB value of at least 10 in an amount of at least 0.001 wt.-%,        based on the total weight of the pharmaceutical dosage form;        and/or    -   the pharmaceutical dosage form is for oral administration;        and/or    -   the pharmaceutical dosage form contains 0.01% to 95% of the        pharmacologically active agent (A); and/or    -   the pharmaceutical dosage form has a weight within the range of        from 0.1 mg to 2,000 mg; and/or    -   the pharmaceutical dosage form contains a polymer with a        molecular weight within the range of from 1,000 g/mol to 15        million g/mol; and/or    -   the pharmaceutical dosage form is a tablet; and/or    -   the pharmaceutical dosage form is prepared by means of wet        granulation or direct tabletting; and/or    -   the pharmaceutical dosage form contains the pharmacologically        active agent according to general formula (I) in a dose of from        10 μg to 50 μg or of from 300 μg to 500 μg; and/or    -   the pharmaceutical dosage form provides immediate release of the        pharmacologically active agent according to general formula (I)        in vitro in accordance with Ph. Eur.; and/or    -   t_(max) is within the range of from 0.5 to 16 h; and/or    -   the ratio AUC_(0-t)/dose is within the range of from 0.5 to 16.5        h/m³; and/or    -   ratio C_(max)/dose is within the range of from 0.06 to 1.69 m⁻³.

In a preferred embodiment, the pharmaceutical dosage form according tothe invention is a tablet, chewable tablet, chewing gum, coated tabletor powder, optionally filled into a capsule, but particularly preferablya tablet.

In another preferred embodiment, the pharmaceutical dosage formaccording to the invention is present in multi-particulate form,preferably in form of a micro-tablet, micro-capsule, granulate, pelletor active-substance crystal, particularly preferably in form of amicro-tablet, granulate or pellet, optionally filled into a capsule orcompressed to form a tablet.

In some especially preferred embodiments, the pharmaceutical dosage formaccording to the invention is a tablet. The tablet can be of any desiredsize. In some preferred embodiments, the tablet has a diameter of 6±3mm, more preferably of 6±2.5 mm, even more preferably of 6±2 mm, stillmore preferably of 6±1.5 mm, most preferably of 6±1 mm, and inparticular of 6±0.5 mm.

The pharmaceutical dosage form according to the invention may containpharmaceutical excipients including conventional antiadherents, binders,disintegrants, fillers, diluents, glidants, lubricants andpreservatives, known to a person skilled in the art.

One suitable antiadherent that may be contained in the pharmaceuticaldosage form is magnesium stearate. In a preferred embodiment, thecontent of the antiadherent is within the range of from 0.001 to 5.0wt.-%, for example 0.01 to 5 wt.-%, 0.1 to 5 wt.-%, 0.1 to 3 wt.-%, 0.1to 2 wt.-%, or even 0.5 to 1.5 wt.-%.

In a preferred embodiment, the pharmaceutical dosage form according tothe invention further contains a binder. Suitable binders include butare not limited to gelatin, cellulose, modified cellulose such asmicrocrystalline cellulose, methyl cellulose, polyvinyl pyrrolidone,starch, sucrose and polyethylene glycol; especially preferred arepolyvinyl pyrrolidone and/or microcrystalline cellulose. In a preferredembodiment, the content of antiadherent is within the range of from0.001 to 30 wt.-%, more preferably 0.1 to 25 wt.-%. In some embodiments,the dosage form comprises 1 to 20 wt.-%, 5 to 20 wt.-%, or 10 to 20wt.-% of binder(s).

In a preferred embodiment, the pharmaceutical dosage form according tothe invention further contains a filler and/or diluent, preferablyselected from the group consisting of but are not limited to cellulose,calcium diphosphate, lactose, sucrose, glucose, mannitol, sorbitol, andcalcium carbonate; especially preferred are micro-crystalline celluloseand lactose. In a preferred embodiment, the content of filler and/ordiluent is within the range of from 0.001 to 90 wt.-%, 0.01 to 85 wt.-%,more preferably 0.1 to 80 wt.-%, most preferably 10 to 75 wt.-%.

In a preferred embodiment, the pharmaceutical dosage form according tothe invention further contains a lubricant such as magnesium stearate,stearic acid and stearin. In a preferred embodiment, the content of thelubricant is within the range of from 0.001 to 5 wt.-%, e.g., from 0.1to 3 wt. %.

In a preferred embodiment, the pharmaceutical dosage form according tothe invention further contains a disintegrant such as cross-linkedsodium carboxymethyl cellulose (croscarmellose sodium), cross-linkedpolyvinyl pyrrolidone and sodium starch glycolate. In a preferredembodiment, the content of the disintegrant is within the range of from0.001 to 5 wt.-%, e.g., from 0.1 to 3 wt. %.

The pharmaceutical dosage form may further contain at least onepreservative. Suitable preservatives include but are not limited toantioxidants, such as vitamin A, vitamin E, vitamin C, retinyl palmitateand selenium; cysteine, methionine, citric acid, sodium citrate, methylparaben and propyl paraben.

In a preferred embodiment, the pharmaceutical dosage form furthercontains a coating, in particular a polymer-based coating, more inparticular a polyvinyl alcohol-based coating such as the onescommercially available under the trade name “Opadry”.

In some preferred embodiments, the pharmaceutical dosage form is atablet which comprises the pharmacologically active agent according tothe general formula (I) (e.g., in an amount from 0.6±0.4 wt.-%, 0.6±0.3wt.-%, 0.6±0.2 wt.-%, 0.6±0.1 wt.-%, 0.04±0.03 wt.-%, 0.04±0.02 wt-%, or0.04±0.01 wt.-%), one or more antiadherents (e.g., magnesium stearate)in an amount from 0.001 to 5.0 wt.-% (e.g., 0.01 to 5 wt.-%, 0.1 to 5wt.-%, 0.1 to 3 wt.-%, 0.1 to 2 wt.-%, or even 0.5 to 1.5 wt.-%), one amore binders (e.g., polyvinyl pyrrolidone and/or microcrystallinecellulose) in an amount from 0.001 to 30 wt.-% (e.g., from 0.1 to 25wt.-%, 1 to 20 wt.-%, 5 to 20 wt.-%, or 10 to 20 wt.-%), and one or morefillers or diluents (e.g., micro-crystalline cellulose and/or lactose)in an amount from 0.001 to 90 wt.-% (e.g., 0.01 to 85 wt.-%, morepreferably 0.1 to 80 wt.-%, most preferably 10 to 75 wt.-%). In someembodiments, the tablet also comprises one or more lubricants (e.g.,magnesium stearate, stearic acid and/or stearin) in an amount from 0.001to 5 wt.-% (e.g., from 0.1 to 3 wt. %) and/or one or more disintegrants(e.g., croscarmellose sodium, cross-linked polyvinyl pyrrolidone and/orsodium starch glycolate) in an amount from 0.001 to 5 wt.-% (e.g., from0.1 to 3 wt. %).

Preferably, the coating protects the pharmaceutical dosage form frommoisture, but dissolves rapidly in gastric juice. More preferably, thecoated dosage form has a disintegration time of less than 5 minutes ingastric juice, more preferably of at most 4.5 minutes, still morepreferably at most 4 minutes, yet more preferably at most 3.5 minutes,even more preferably at most 3 minutes, most preferably at most 2.5minutes and in particular at most 2 minutes.

For the manufacture of the pharmaceutical dosage forms according to theinvention, the various solid auxiliary substances and thepharmacologically active agent according to general formula (I) arepreferably homogenized, processed by means of wet, dry or fusiongranulation to form granulates, and compressed to form tablets.Alternatively, they are manufactured by direct tabletting of theauxiliary substances and the pharmacologically active agent according togeneral formula (I).

In a preferred embodiment, the pharmaceutical dosage form is prepared bymeans of wet granulation from a granulating fluid containing thepharmacologically active agent according to general formula (I), inparticular from an aqueous granulating fluid containing saidpharmacologically active agent and the surfactant. Preferably, theresulting granulating fluid is then top-sprayed or bottom-sprayed onto asolid formulation containing at least one auxiliary substance to yieldcompressible granules, which may optionally be mixed with furtherauxiliary substances before being compressed to tablets.

A further aspect of the invention relates to the pharmaceutical dosageform according to the invention as described above for use in thetreatment of pain.

A further aspect of the invention relates to a method of treating paincomprising the twice daily, once daily, or less frequently, preferablyoral administration of the pharmaceutical dosage form according to theinvention to a subject in need thereof.

Preferably, the pain is selected from acute, visceral, neuropathic orchronic pain.

In another particular preferred embodiment,

-   -   the pharmaceutical dosage form contains 0.01% to 95% of the        pharmacologically active agent (A); and/or    -   the pharmaceutical dosage form has a weight within the range of        from 0.1 mg to 2,000 mg; and/or    -   the pharmaceutical dosage form is adapted for oral        administration; and/or    -   the pharmaceutical dosage form contains the pharmacologically        active agent according to general formula (I) in a dose of from        10 μg to 50 μg or from 25 μg to 80 μg; and/or    -   the pharmacologically active agent according to general        formula (I) is contained in the dosage form in an amount that is        sub-therapeutic with regard to a single administration of the        dosage form; and/or    -   the pharmacologically active agent according to general        formula (I) is contained in the dosage form in a quantity that        is sub-therapeutic with regard to acute pain treatment; and/or    -   the pharmacologically active agent according to general        formula (I) is contained in the dosage form in a quantity such        that initial dose titration is not required; and/or    -   the pharmacologically active agent according to general        formula (I) is contained in the dosage form in a quantity such        that number of adverse events that occur during administration        of the dosage form is decreased compared to a dosage form        comprising a pure μ-opioid receptor agonist, such as morphine in        a therapeutically equally effective amount; and/or    -   t_(max) is within the range of from 2 to 10 h, preferably from 2        to 6 h; and/or    -   the ratio AUC_(0-t)/dose is within the range of from 0.5 to 16.5        h/m³, preferably from 6 to 12 h/m³; and/or    -   ratio C_(max)/dose is within the range of from 0.06 to 1.69 m⁻³,        preferably within the range of from 0.3 to 1.3 m⁻³; and/or    -   the highest plasma concentration of the pharmacological agent        reached after once daily administration of the pharmaceutical        dosage form for at least 5 consecutive days is within the range        from 10 to 120 μg/m³, preferably 20 to 80 μg/m³.

A further aspect of the invention relates to a method of treatingneuropathic pain, preferably chronic neuropathic pain comprising theadministration of a pharmacologically effective amount of thepharmacologically active agent according to general formula (I) or aphysiologically acceptable salt thereof; preferably the once daily,preferably oral administration of the pharmaceutical dosage formaccording to the invention; to a subject in need thereof.

Preferably, the pain is chronic neuropathic pain or acute neuropathicpain, peripheral neuropathic pain or central neuropathic pain,mononeuropathic pain or polyneuropathic pain. When the neuropathic painis chronic, it may be chronic peripheral neuropathic pain or chroniccentral neuropathic pain, in a preferred embodiment chronic peripheralmononeuropathic pain or chronic central mononeuropathic pain, in anotherpreferred embodiment chronic peripheral polyneuropathic pain or chroniccentral polyneuropathic pain. When the neuropathic pain is acute, it maybe acute peripheral neuropathic pain or acute central neuropathic pain,in a preferred embodiment acute peripheral mononeuropathic pain or acutecentral mononeuropathic pain, in another preferred embodiment acuteperipheral polyneuropathic pain or acute central polyneuropathic pain.

Preferably, the pain is chronic neuropathic pain. For the purpose of thespecification, neuropathic pain is pain that originates from nervedamage or nerve malfunction. It becomes classified as chronicneuropathic pain when it is present for more than 3 months.

In another particular preferred embodiment of the invention,

-   -   the pharmaceutical dosage form contains 0.01% to 95% of the        pharmacologically active agent (A); and/or    -   the pharmaceutical dosage form has a weight within the range of        from 0.1 mg to 2,000 mg; and/or    -   the pharmaceutical dosage form is adapted for oral        administration; and/or    -   the pharmaceutical dosage form contains the pharmacologically        active agent according to general formula (I) in a dose of from        200 μg to 800 μg or from 300 μg to 500 μg; and/or    -   the pharmacologically active agent according to general        formula (I) is contained in the dosage form in an amount that is        sub-therapeutic with regard to a single administration of the        dosage form; and/or    -   the pharmacologically active agent according to general        formula (I) is contained in the dosage form in a quantity such        that initial dose titration is not required; and/or    -   the pharmacologically active agent according to general        formula (I) is contained in the dosage form in a quantity such        that number of adverse events that occur during administration        of the dosage form is decreased compared to a dosage form        comprising a pure μ-opioid receptor agonist, such as morphine in        a therapeutically equally effective amount; and/or    -   t_(max) is within the range of from 2 to 10 h, preferably from 5        to 7 h; and/or    -   the ratio AUC_(0-t)/dose is within the range of from 0.5 to 16.5        h/m³, preferably from 6 to 12 h/m³; and/or    -   ratio C_(max)/dose is within the range of from 0.06 to 1.69 m⁻³,        preferably within the range of from 0.30 to 1.30 m⁻³.

A further aspect of the invention relates to a method of treatingnociceptive pain, preferably acute or chronic nociceptive pain,comprising the once daily, preferably oral administration of thepharmaceutical dosage form according to the invention to a subject inneed thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention will be described in further detail hereinafter withreference to the accompanying drawings, in which:

FIG. 1 shows the averaged numerical rating scale (NRS) values measuredover a 24 hour period after administration of different single doses ofthe compound according to formula (I′b) (200, 400, 600 μg) compared toslow release morphine and placebo in patients with acute post-operativepain following orthopedic surgery (bunionectomy).

FIG. 2 shows the release profile of the pharmacologically active agentaccording to general formula (I′b) from the pure solid itself (A), fromsolid formulations containing the active agent and a polymer (Kollidon90; B) and from solid solutions containing the active agent, a polymer(Kollidon 90 or Kollidon VA 64) and a surfactant (Pluronic F68 or Tween80; C-E) in hydrochloric acid (0.1 N). The X-Axis refers to the time inminutes and the Y-Axis refers to the amount of dissolved active agent inpercent in relation to the whole amount of active agent originallycontained in the dosage form.

FIG. 3 shows the release profile of the pharmacologically active agentaccording to general formula (I′b) from the pure solid itself (A), froma solid formulation containing the active agent and a polymer (KollidonVA 64; B) and from solid solutions containing the active agent, apolymer (Kollidon VA 64) and a surfactant (Tween 80; C) in hydrochloricacid (0.1 N). The X-Axis refers to the time in minutes and the Y-Axisrefers to the amount of dissolved active agent in percent in relation tothe whole amount of active agent originally contained in the dosageform.

FIG. 4 shows the X-ray powder diffractogram of a solid solutioncontaining the pharmacologically active agent according to generalformula (I′b), polymer Kollidon VA64 and surfactant Tween 80 beforebeing objected to a storage stability test.

FIG. 5 shows the X-ray powder diffractogram of a solid solutioncontaining the pharmacologically active agent according to generalformula (I′b), polymer Kollidon VA64 and surfactant Tween 80 after 4weeks of storage at 25° C. and 60% relative humidity.

FIG. 6 shows the X-ray powder diffractogram of a solid solutioncontaining the pharmacologically active agent according to generalformula (I′b), polymer Kollidon VA64 and surfactant Tween 80 after 4weeks of storage at 30° C. and 65% relative humidity.

FIG. 7 shows the average daily pain changes (change of NRS value) over a5-day period after administration of daily doses of the compoundaccording to formula (I′b) (40 μg, 120 μg) compared to placebo inpatients with painful diabetic neuropathy.

FIG. 8 shows the average daily pain changes (change of NRS value) over a5-day period after administration of daily doses of the compoundaccording to formula (I′b) (80 μg, 200 μg) compared to placebo inpatients with painful diabetic neuropathy.

FIG. 9 shows the average daily pain changes (change of NRS value) over a5-day period after administration of daily doses of the compoundaccording to formula (I′b) (100 μg) compared to placebo and morphineslow release (60 mg) in patients with painful diabetic neuropathy.

FIG. 10 shows the mean maximum plasma concentration of the compoundaccording to formula (I′b) measured on the last day of a 5-day oncedaily dosing period in comparison to the plasma concentration measured 8to 10 days later at the end of a wash-out phase.

EXAMPLES

The following examples further illustrate the invention but are not tobe construed as limiting its scope.

Example 1a

In order to find a suitable combination of oil, surfactant andhydrophilic solvent, the saturation concentration of thepharmacologically active agent according to formula (I′b) was firstdetermined in a variety of oils as follows:

A saturated solution of said pharmacologically active agent was made bysuspending an appropriate amount in 5 g of the respective medium. Afterremoving any trace of undissolved material by filtration through asintered glass filter (0.45 μm and 0.22 μm), the remaining solution wasconcentrated under vacuum. The vacuum was maintained until all obvioustraces of solvent had been removed, and the flask was then stored overnight under high vacuum. The weight of the remaining compound wasdetermined and the saturation concentration of (I′b) in the respectiveoil was calculated.

The results are displayed in the following Table 4:

TABLE 4 Amount of (I′b) Saturation Amount of (before concentration OilSolvent [g] filtration) [g/5 g] [mg/g] Oleic acid 5 0.26061 30.0060Caprylic acid 5 0.13559 26.0920 Ethyl oleate 5 0.01373 0.8043 Soybeanoil 5 0.01587 0.8739 Peanut oil 5 0.01400 0.9898 Miglyol 812 5 0.010750.9400 Captex 355 5 0.01221 0.9615 Labrafac WL 1349 5 0.01207 0.9349Capryol 90 5 0.02153 3.3547 Capric acid 5 0.12076 23.5590 Maisine 35-150° C. 5 0.04688 3.7418 Labrafil M 1944 CS 5 0.04197 4.8707 Labrafil M2125 CS 5 0.04855 5.0369 Myristic Acid 5 0.01934 3.7878

The saturation concentration of compound (I′b) was determinedaccordingly in a variety of surfactants at 50° C. (filter: 0.45 μm). Theresults are displayed in the following Table 5:

TABLE 5 Amount of (I′b) Saturation Amount of (before concentrationSurfactant Solvent [g] filtration) [g/5 g] [mg/g] TPGS (PEG-Vit. 50.04921 8.0491 E succhinate) Gelucire 44/14 5 0.04265 3.7280 Gelucire50/13 65° C. 5 0.05182 10.0160 Cremophor EL 5 0.04342 9.0519 CremophorRH40 5 0.04884 9.6462 Tween 20 5 0.03895 7.4428 Tween 60 5 0.041518.7866 Tween 80 5 0.02177 4.2641 Labrasol 5 0.05707 10.7540 Glycerolmonooleate 5 0.01517 2.9428 (Peceol) Solutol HS15 5 0.04921 10.1650

As suitable oils oleic acid, caprylic acid and capric acid wereidentified (solubility>20 mg/g solvent), whereas labrasol, solutol HS 15and gelucire 50/13 were identified as suitable surfactants(solubility>10 mg/g solvent).

The saturation concentration of compound (I′b) was determinedaccordingly in ethanol and selected propylene glycols. The results aredisplayed in the following Table 6:

TABLE 6 Amount of (I′b) Saturation Amount of (before concentrationSolvent Solvent [g] filtration) [g/5 g] [mg/g] Ethanol 5 0.01498 0.1458Propylenglycol 5 0.01858 0.1084 PEG 400 5 0.03061 4.7791 PEG 1500 50.02565 8.2633 PEG 4000 5 0.03992 7.6528

Example 1b

According to example 1a, the saturation concentration of compound (I′b)was determined in two-component formulations of one oil (oleic acid,caprylic acid or capric acid) and one surfactant (labrasol, tween 60,solutol HS 15 and gelucire 50/13). Since these two-componentformulations are solid at room-temperature, these solubility studieswere conducted at 50° C. If these two-component formulations containsufficient amounts of (I′b), they are also liquid at room temperature. Asaturated solution of the two-component formulation is a liquid, aswell.

TABLE 7 Amount of (I′b) Saturation Ratio (before fil- concentra-Formulation surfactant/oil tration) [g/5 g] tion [mg/g]Labrasol/Caprylic Acid  5:95 0.10308 17.24 Labrasol/Caprylic Acid 10:900.09126 16.87 Labrasol/Caprylic Acid 20:80 0.09185 15.89Labrasol/Caprylic Acid 40:60 0.07167 12.3 Labrasol/Oleic Acid  5:950.14580 28.76 Labrasol/Oleic Acid 10:90 0.12596 22.45 Labrasol/OleicAcid 20:80 0.01154 22.85 Labrasol/Oleic Acid 40:60 0.09044 19.57Tween60/Caprylic Acid  5:95 0.09633 18.85 Tween60/Caprylic Acid 10:900.09832 18.98 Tween60/Caprylic Acid 20:80 0.02941 7.36 Tween60/CaprylicAcid 40:60 0.03410 6.59 Solutol HS15/Caprylic Acid  5:95 0.09329 18.32Solutol HS15/Caprylic Acid 10:90 0.08622 16.14 Solutol HS15/CaprylicAcid 20:80 0.07366 15.13 Solutol HS15/Caprylic Acid 40:60 0.05841 12.39Solutol HS15/Capryol 90  5:95 0.05355 3.008 Solutol HS15/Capryol 9010:90 0.04418 3.138 Solutol HS15/Capryol 90 20:80 0.05118 3.650 SolutolHS15/Capryol 90 40:60 0.04335 4.561 Gelucire44/14/Capryol 90  5:950.04786 3.060 Gelucire44/14/Capryol 90 10:90 0.04515 3.312Gelucire44/14/Capryol 90 20:80 0.04667 4.047 Gelucire44/14/Capryol 90*40:60 0.06647 6.068

Accordingly, the saturation concentration of (I′b) in the followingthree-component formulation was determined:

Solutol ® HS 15 60% (w/w) Miglyol 812 20% (w/w) Ethanol (abs.) 20% (w/w)

The saturation concentration of (I′b) in said formulation was determinedto be 1.3 mg/g.

Example 2

The phase behavior of the oil/surfactant mixtures according to example1b was determined in presence of an aqueous medium.

For that purpose, 20 g of the respective two-component mixture was madeby mixing the respective amounts of oil and surfactant. 0.5 g of themixture was then added to 250 g of water or 250 g of gastric juice,respectively.

The formation of an emulsion in the aqueous medium was observed,described visually (qualitative extent of turbidity) and measuredquantitatively by means of a conventional turbidity photometer.

TABLE 8 ratio surfactant/oil Appearance of the formulation (clear,turbid, colour, . . .) [wt.-%/ in absence of in 250 mL wt.-%] aqueousmedia [TE/F] in 250 mL H₂O [TE/F] gastric juice Labrasol/Caprylic clear25 emulsion 32 oil droplets, Acid turbid Labrasol/Caprylic 10:90 clear23 emulsion 2.9 oil droplets, Acid clear Labrasol/Caprylic 20:80 clear21 emulsion 11 oil droplets, Acid clear Labrasol/Caprylic 40:60 clear 82emulsion 15 oil droplets, Acid clear Labrasol/Oleic  5:95 clear 36emulsion, clear 12.2 oil droplets, Acid turbid Labrasol/Oleic 10:90clear 46 emulsion, clear 19 oil droplets, Acid turbid Labrasol/Oleic20:80 clear 41 emulsion, clear 33 oil droplets, Acid turbidLabrasol/Oleic 40:60 clear 124 emulsion, clear 71 oil droplets, Acidturbid Labrasol/Capric  5:95 solid, white, crystalline 28 n.d. 9 Solid,partly Acid fibrous matter Labrasol/Capric 10:90 solid, white,crystalline 34 n.d. 7.7 Solid, partly Acid fibrous matterLabrasol/Capric 20:80 solid, white, crystalline 27 n.d. 10.3 Solid,partly Acid fibrous matter Labrasol/Capric 40:60 solid, white, clear 60n.d. 11 Solid, partly Acid fibrous matter Tween60/Caprylic  5:95 clear,slightly 33 turbid, 19 small droplets, Acid yellowish drop formationturbid Tween60/Caprylic 10:90 clear, slightly 34 turbid, 36 droplets,turbid Acid yellowish drop formation Tween60/Caprylic 20:80 clear,yellowish 69 opaque 80 flocculate Acid Tween60/Caprylic 40:60 clear,deep yellow 162 turbid, no drop 155 Turbid, no Acid formation visibledrop formation visible Tween60/Oleic  5:95 clear, slightly 404 milky,upper layer, 350 flocculate Acid yellowish flocculate Tween60/Oleic10:90 clear, slightly >680 milky, upper layer, 776 flocculate Acidyellowish flocculate Tween60/Oleic 20:80 clear, slightly 614 milky,upper layer, 876 flocculate Acid yellowish flocculate Tween60/Oleic40:60 clear, slightly 910 milky, upper layer, 520 flocculate Acidyellowish flocculate Tween60/Capric  5:95 solid, yellowish-white, 34solid, fibrous 17 solid upper Acid crystalline layer, flocculateTween60/Capric 10:90 Solid, yellowish-white, 35 containing solid 25solid upper Acid crystalline matter layer, flocculate Tween60/Capric20:80 solid, yellowish-white, 72 deeply turbid 85 solid upper Acidcrystalline layer, flocculate Tween60/Capric 40:60 Solid,yellowish-white 646 turbid, no drop 279 solid upper Acid formationvisible layer, flocculate Solutol HS15/  5:95 clear 27 floating oilydrops 8.1 oil droplets Caprylic Acid Solutol HS15/ 10:90 clear 12.4floating oily drops 11 oil droplets Caprylic Acid Solutol HS15/ 20:80clear 28 emulsoid, slightly 18 emulsoid, Caprylic Acid turbid smalldroplets Solutol HS15/ 40:60 clear 54 opaque, (micro- 98 opaque CaprylicAcid emulsion) (micro- emulsion) Solutol HS15/  5:95 clear 55 dropformation, 30 large droplets Oleic Acid opaque Solutol HS15/ 10:90 clear36 flocculate, turbid 60 flocculate Oleic Acid Solutol HS15/ 20:80 clear704 flocculate, turbid 450 flocculate Oleic Acid Solutol HS15/ 40:60 2phases: clear, turbid 1267 flocculate, turbid 777 flocculate, Oleic Aciddeeply turbid Solutol HS15/  5:95 solid, white, clear 8.5 needles 11.4solid upper Capric Acid layer Solutol HS15/ 10:90 solid, white, clear 21needles 8.8 solid upper Capric Acid layer Solutol HS15/ 20:80 solid,white, clear 23 needles 13.7 solid upper Capric Acid layer Solutol HS15/40:60 2 phases: liquid, clear; 144 turbid, upper layer 93 small crystalCapric Acid crystalline, white needles Gelucire 50/13/  5:95 Clear 26transparent, small 26 emulsoid, Caprylic Acid drops turbid Gelucire50/13/ 10:90 Clear; crystalline, 12.1 transparent, small 24 emulsoid,Caprylic Acid white, precipitate drops turbid Gelucire 50/13/ 20:80Clear; crystalline, 19 transparent, drops of 65 emulsoid, Caprylic Acidwhite, precipitate variable size turbid Gelucire 50/13/ 40:60 Clear;crystalline, 90 turbid, flocculate 87 opaque, Caprylic Acid white,precipitate particles Gelucire 50/13/  5:95 Clear; crystalline, 335upper layer, white 450 emulgator Oleic Acid white, precipitate foamseems not to be soluble Gelucire 50/13/ 10:90 Clear; crystalline, 465upper layer, white 1031 emulgator Oleic Acid white, precipitate foamseems not to be soluble Gelucire 50/13/ 20:80 Clear; crystalline, 1050upper layer, white 260 emulgator Oleic Acid white, precipitate, foamseems not to highly viscous be soluble Gelucire 50/13/ 40:60 Clear;crystalline, 403 upper layer, white 263 emulgator Oleic Acid whiteprecipitate, foam seems not to highly viscous be soluble Gelucire 50/13/ 5:95 solid, white, crystalline 7.3 Solid upper layer 32 n.d. CapricAcid Gelucire 50/13/ 10:90 solid, white, crystalline 21 Solid upperlayer 57 n.d. Capric Acid Gelucire 50/13/ 20:80 solid, white,crystalline 62 Solid upper layer 58 n.d. Capric Acid Gelucire 50/13/40:60 solid, white, crystalline 520 Solid upper layer 433 n.d. CapricAcid

The extent of turbidity is an indication for the size of the droplets ofan emulsion. Micro- or nanoemulsions appear clear to the naked eye anddo not show turbidity, since the size of the droplets is too small forrefracting visible light.

As a result, two-component mixtures of labrasol and caprylic acid,labrasol and oleic acid, tween 60 and caprylic acid, as well as solutolHS 15 and caprylic acid formed clear solutions in absence of any aqueousmedia. All of them formed emulsions in water and gastric juice. Tween60/caprylic acid (40:60) and solutol HS 15/caprylic acid (40:60) showedthe best phase behavior in aqueous media forming clear microemulsionswhithout visible drop formation in water and in gastric juice.

Emulsions which gave promising results in the previous study were thensubjected to particle size analysis (using a laser-based particle sizeanalyzer type Zetasizer NanoZS, Malvern Instruments) with a particlesize measurement range of 0.02 to 2,000 μm. Particle size was calculatedfrom the volume size distribution.

TABLES 9-17 Labrasol-oleic acid 40:60 in 250 g H₂O Mea- Peak 1 Peak 1Peak 2 Peak 2 Peak 3 Peak 3 sure- diame- occurence diame- occurencediame- occurence ment ter [nm] [%] ter [nm] [%] ter [nm] [%] 1 326.2 3.1100.2 96.9 0 0 2 169.8 100 0 0 0 0 3 2956 0.1 152 99.9 0 0Labrasol-oleic acid 40:60 in 250 g gastric juice Mea- Peak 1 Peak 1 Peak2 Peak 2 Peak 3 Peak 3 sure- diame- occurence diame- occurence diame-occurence ment ter [nm] [%] ter [nm] [%] ter [nm] [%] 1 242.6 100 0 0 00 2 243.8 100 0 0 0 0 3 265.8 100 0 0 0 0 Labrasol-oleic acid 5:95 in250 g H₂O Mea- Peak 1 Peak 1 Peak 2 Peak 2 Peak 3 Peak 3 sure- diame-occurence diame- occurence diame- occurence ment ter [nm] [%] ter [nm][%] ter [nm] [%] 1 0 0 0 0 0 0 2 6.411 100 0 0 0 0 3 19.35 100 0 0 0 0Solutol- caprylic acid 40:60 in 250 g H₂O Mea- Peak 1 Peak 1 Peak 2 Peak2 Peak 3 Peak 3 sure- diame- occurence diame- occurence diame- occurencement ter [nm] [%] ter [nm] [%] ter [nm] [%] 1 289.7 8.4 2938 0 94.4 91.62 154.9 96 772.2 3.2 0 0 3 175.7 97.6 982.8 2.4 0 0 Solutol- caprylicacid 40:60 in 250 g gastric juice Mea- Peak 1 Peak 1 Peak 2 Peak 2 Peak3 Peak 3 sure- diame- occurence diame- occurence diame- occurence mentter [nm] [%] ter [nm] [%] ter [nm] [%] 1 142 100 0 0 0 0 2 107.8 100 0 00 0 3 206 100 0 0 0 0 Tween 60- caprylic acid 40:60 in 250 g H₂O Mea-Peak 1 Peak 1 Peak 2 Peak 2 Peak 3 Peak 3 sure- diame- occurence diame-occurence diame- occurence ment ter [nm] [%] ter [nm] [%] ter [nm] [%] 162.06 100 0 0 0 0 2 79.3 100 0 0 0 0 3 53.32 100 0 0 0 0 Tween 60-caprylic acid 40:60 in 250 g gastric juice Mea- Peak 1 Peak 1 Peak 2Peak 2 Peak 3 Peak 3 sure- diame- occurence diame- occurence diame-occurence ment ter [nm] [%] ter [nm] [%] ter [nm] [%] 1 52.24 99.6 204.50.4 0 0 2 49.07 99.2 146.6 0.8 0 0 3 46.15 98.4 117.3 1.6 546.6 0 Tween60- caprylic acid 20:80 in 250 g H₂O Mea- Peak 1 Peak 1 Peak 2 Peak 2Peak 3 Peak 3 sure- diame- occurence diame- occurence diame- occurencement ter [nm] [%] ter [nm] [%] ter [nm] [%] 1 151.3 0.1 28.37 99.9 0 0 2198.2 100 0 0 0 0 3 186.3 100 0 0 0 0 Tween 60- caprylic acid 20:80 in250 g gastric juice Mea- Peak 1 Peak 1 Peak 2 Peak 2 Peak 3 Peak 3 sure-diame- occurence diame- occurence diame- occurence ment ter [nm] [%] ter[nm] [%] ter [nm] [%] 1 1218 0.2 59.09 99.8 0 0 2 442.2 100 0 0 0 0 3892.6 0.3 65.8 99.7 0 0

Example 3

The stability of compound (I′b) in a variety of oils and surfactants wasdetermined under stress (elevated temperature):

For this study, 50 mg of said compound was dissolved in 50 g of therespective medium and objected to elevated temperatures for 6 weeks. Thesame study was conducted using 500 mg of compound (I′b). After thisperiod, the corresponding demethylated derivative (I′a) and/or thecorresponding cis/trans-isomerized derivatives were identified as maindegradation products.

The results show that the lowest degradation occurred in Solutol,Capryol and Gelucire. In general, the degradation was lower in thehigher dosed samples.

TABLE 18 50 mg 50 mg 50 mg 50 mg 41 mg 50 mg 50 mg 50 mg in 50 g in 50 gin 50 g in 50 g in 41 g in 50 g in 50 g in 50 g Oleic acid Caprylic acidCapric acid Gelucire Tween 60 Labrasol Solutol Capryol Content of (I′b)in the assay 170.01% 100.39% 186.13% 100.46% 93.05% 99.55% 100.11%99.70% after 2 weeks at 25° C. 175.72% 101.01% 101.68% 101.29% 96.73%99.94% 102.72% 101.06% 2 weeks at 40° C. F. 176.43% 100.68% 101.10%101.09% 92.43% 95.69% 102.13% 100.67% 4 weeks at 25° C. 156.64% 101.43%97.62% 102.62% 92.22% 98.33% 100.25% 99.46% 4 weeks at 40° C. F. 143.56%101.11% 91.46% 102.56% 89.09% 91.93% 100.08% 99.07% 6 weeks at 25° C.156.85% 101.69% 120.87% 100.75% 91.45% 97.63% 100.45% 99.86% 6 weeks at40° C. F. 141.66% 100.93% 94.19% 100.41% 86.93% 89.87% 99.69% 99.36%Purity in the assay 93.85% 95.26% 94.93% 99.34% 96.63% 98.36% 98.83%97.44% compound (I′a) 4.93% — — 0.66% — 1.64% — 0.22% cis isomer of(I′a) — — — — — — — — Amount other 1.23% 4.74% 5.07% — 3.37% — 1.08%2.34% cis isomer of (I′b) — — — — — — 0.09% — after 2 weeks at 25° C.93.22% 95.19% 94.71% 99.60% 97.01% 98.22% 98.92% 97.51% compound (I′a)5.75% — — — — 1.71% — 0.13% cis isomer of (I′a) — — — — — — — — amountother 1.03% 4.81% 3.95% 0.40% 2.99% 0.06% 1.01% 2.36% cis isomer of(I′b) — — 1.35% — — — 0.07% — after 2 weeks at 40° C. F. 88.45% 95.12%94.57% 99.30% 94.62% 95.11% 98.81% 97.37% compound (I′a) 9.69% — — — —4.29% — 0.22% cis isomer of (I′a) — — — — — — — — amount other 1.77%4.88% 4.13% 0.70% 5.38% 0.61% 1.03% 2.41% cis isomer of (I′b) 0.10% —1.30% — — — 0.17% — after 4 weeks at 25° C. 89.17% 94.51% 98.96% 99.36%96.96% 97.07% 99.12% 99.29% compound (I′a) 10.72% 0.05% — 0.59% — 2.82%0.04% 0.20% cis isomer of (I′a) — — 1.04% 0.03% — 0.03% — — amount other0.12% 5.45% — 0.03% 3.03% 0.08% 0.84% 0.51% cis isomer of (I′b) — — — —— — — — after 4 weeks at 40° C. F. 84.27% 97.30% 99.13% 98.96% 94.12%92.02% 98.90% 98.10% compound (I′a) 15.48% 0.08% — 0.98% — 7.87% 0.16%0.34% cis isomer of (I′a) — — — 0.03% — 0.02% — amount other 0.25% 2.62%0.87% 0.03% 5.87% 0.09% 0.95% 1.57% cis isomer of (I′b) — — — — — — — —after 6 weeks at 25° C. 88.41% 96.57% 93.36% 99.44% 96.89% 96.71% 99.15%98.54% compound (I′a) 11.52% 0.32% 5.63% 0.53% 2.78% 3.24% 0.08% 0.16%cis isomer of (I′a) — — 0.95% 0.03% — — — — amount other 0.07% 3.11%0.06% — 0.33% 0.04% 0.77% 1.29% cis isomer of (I′b) — — — — — — — —after 6 weeks at 40° C. F. 84.99% 96.06% 92.74% 98.81% 93.60% 90.17%98.82% 98.22% compound (I′a) 14.45% 0.5% 6.34% 1.17% 5.99% 9.78% 0.20%0.37% cis isomer of (I′a) — — 0.92% 0.02% — — — — amount other 0.57%3.43% — — 0.41% 0.05% 0.98% 1.42% cis isomer of (I′b) — — — — — — — —500 mg 500 mg 500 mg 400 mg 400 mg 400 mg 350 mg 100 mg in 50 g in 50 gin 50 g in 50 g in 50 g in 50 g in 50 g in 50 g Oleic acid Caprylic acidCapric acid Gelucire Labrasol Solutol Tween 60 Capryol Content of (I′b)in the assay 102.13% 100.13% 101.20% 100.93% 98.55% 98.18% 99.41% 99.46%after 2 weeks at 25° C. 102.61% 100.12% 102.50% 102.67% 97.36% 100.21%94.96% 100.97% 2 weeks at 40° C. F. 100.48% 100.22% 102.19% 101.53%97.09% 89.65% 105.18% 101.57% 4 weeks at 25° C. 96.79% 99.46% 98.89%100.90% 97.63% 98.41% 99.26% 100.10% 4 weeks at 40° C. F. 95.70% 99.62%100.76% 100.54% 95.60% 80.83% 89.08% 99.63% 6 weeks at 25° C. 93.24%99.77% 112.08% 99.77% 97.41% 99.16% 78.26% 99.62% 6 weeks at 40° C. F.94.39% 99.02% 100.26% 99.16% 96.52% 88.83% 84.54% 99.22% Purity in theassay 94.62% 99.35% 98.94% 99.91% 98.78% 99.82% 99.02% 98.00% compound(I′a) 4.62% — — 0.09% 1.22% — 0.81% 0.29% cis isomer of (I′a) — — — — —— — — Amount other 0.76% 0.65% 1.06% — — 0.11% — 1.71% cis isomer of(I′b) — — — — — 0.07% 0.17% — after 2 weeks at 25° C. 94.40% 99.61%100.00% 99.91% 98.77% 99.81% 98.98% 98.79% compound (I′a) 4.96% — —0.09% 1.23% — 0.73% 0.13% cis isomer of (I′a) — — — — — — — — amountother 0.64% 0.39% — — — 0.12% 0.30% 1.08% cis isomer of (I′b) — — — — —0.06% — — after 2 weeks at 40° C. F. 91.26% 99.61% 99.92% 99.90% 97.75%99.74% 98.09% 98.67% compound (I′a) 7.09% — — 0.10% 2.25% 0.06% 1.26%0.20% cis isomer of (I′a) — — — — — — — — amount other 1.57% 0.39% — — —0.09% 0.65% 1.13% cis isomer of (I′b) 0.08% — 0.08% — — 0.11% — — after4 weeks at 25° C. 93.55% 99.75% 99.91% 99.86% 98.10% 99.78% 98.82%98.99% compound (I′a) 6.33% — — 0.11% 1.87% 0.05% 0.04% 0.15% cis isomerof (I′a) — — — — — 0.06% — — amount other 0.12% 0.25% 0.09% 0.03% 0.03%0.12% 0.84% 0.85% cis isomer of (I′b) — — — — — — — — after 4 weeks at40° C. F. 91.70% 99.71% 99.90% 99.79% 96.79% 99.64% 97.99% 98.79%compound (I′a) 8.30% 0.03% 0.02% 0.17% 3.17% 0.10% 1.76% 0.29% cisisomer of (I′a) — — — — — 0.15% 0.25% amount other 0.10% 0.25% 0.08%0.03% 0.04% 0.11% — 0.93% cis isomer of (I′b) — — — — — — — — after 6weeks at 25° C. 93.26% 99.72% 99.85% 99.89% 97.92% 99.71% 98.79% 99.05%compound (I′a) 6.65% 0.02% 0.05% 0.08% 2.06% 0.11% 1.08% 0.16% cisisomer of (I′a) — 0.21% 0.05% 0.03% 0.02% 0.13% 0.13% — amount other0.10% 0.05% 0.04% — — 0.06% — 0.79% cis isomer of (I′b) — — — — — — — —after 6 weeks at 40° C. F. 92.03% 99.70% 99.01% 99.82% 96.52% 99.80%97.99% 98.91% compound (I′a) 7.88% 0.04% 0.31% 0.16% 3.46% 9.78% 1.85%0.27% cis isomer of (I′a) — 0.21% 0.61% 0.02% 0.02% — 0.16% — amountother 0.09% 0.04% 0.08% — — 0.05% — 0.83% cis isomer of (I′b) — — — — —— — —

Example 4

The ability and performance of Solutol HS 15/Capryol mixtures andGelucire 44/14/Capryol mixtures to (micro)emulsify, each containingcompound (I′b), was determined next.

For that purpose, 20 g of the respective formulation was made by mixingthe respective amounts of oil, surfactant and compound (I′b). 0.5 g ofthe resulting formulation were then exposed to 250 mL of water or 250 mLof gastric juice and the resulting emulsion formation was measuredqualitatively (visually) and quantitatively by means of a conventionalturbidity photometer.

TABLE 19 ratio surfactant/oil Solubility of (I′b) Appearance of theformulation (clear, turbid, colour, . . .) [wt.-%/ (in surfactant/oil)in absence of in 250 mL wt.-%] [mg/g] aqueous media [TE/F] in 250 mL H₂O[TE/F] gastric juice Solutol HS/  5:95 3.01 clear 169 emulsion, 313milky, opaque, Capryol transparent, uniformly turbid slightly turbidSolutol HS/ 10:90 3.14 clear 430 emulsion, 411 milky, opaque Capryolmore turbid than previous sample Solutol HS/ 20:80 3.65 clear 180turbid, floating 238 transparent, Capryol particles, slightly opaque,vanish during microemulsion shaking Solutol HS/ 40:60 4.56 clear 66turbid, floating 56 transparent, Capryol particles, microemulsion,vanish during more turbid than shaking previous sample Gelucire  5:953.06 clear 101 clear, emulsion 136 Turbid with 44/14/ particles, ratherCapryol suspension Gelucire 10:90 3.31 transparent with 85 slightly 290Turbid with 44/14/ streaks opaque, particles, rather Capryol emulsionsuspension Gelucire 20:80 4.05 white, solid, 136 opaque, 338 Turbid with44/14/ flocculate, turbid emulsoid particles, rather Capryol suspensionGelucire 40:60 6.07 Solid and liquid 31 milky, 50 Turbid with 44/14/parts at 25° C., emulsoid particles, rather Capryol saturated suspensionsolution of (I′b) is liquid

The formation of a microemulsion was observed in those samples whichcontained Solutol HS 15 and Capryol in ratios of 20:80 and 40:60,respectively.

Example 5

A formulation was formulated from the following composition:

Solutol ® HS 15 60% (w/w) Miglyol 812 20% (w/w) Ethanol (abs.) 20% (w/w)

By adding the appropriate amount of compound (I′a) to the saidformulation, solutions of three different concentrations were prepared:

TABLE 20 C-1 (placebo) I-1 I-2 I-3 Formulation 1 mL 1 mL 1 mL 1 mLCompound — 0.1 mg 1.0 mg 10 mg (1′a) Concentration 0.01 wt.-% 0.1 wt.-%1.0 wt.-% of (1′a) in the formulation

1 mL of each of these mixtures was diluted with 20 mL of water.Additional water was sequentially added to the respective solution in 5mL portions and the turbidity process was analyzed by means of aconventional turbidity spectrometer:

TABLE 21 [TE/F] C-1 (placebo) I-1 I-2 I-3 +0 mL H₂O 58 54 57 55 +5 mLH₂O 51 47 51 47 +10 mL H₂O 44 42 49 41 +15 mL H₂O 40 36 42 37 +20 mL H₂O36 29 36 32 +25 mL H₂O 32 27 32 29 +30 mL H₂O 30 25 28 26 +35 mL H₂O 2823 27 24 +40 mL H₂O 25 21 27 24 +45 mL H₂O 24 20 22 21 +50 mL H₂O 22 1921 19 +55 mL H₂O 21 17.7 20 18 +60 mL H₂O 20 16.7 20 17.3 +65 mL H₂O 1916.2 20 16.4 +70 mL H₂O 18.1 15.4 16.9 15.5 +75 mL H₂O 17.5 14.5 15.815.2 +80 mL H₂O 16.2 14.2 15.4 14 +85 mL H₂O 15.9 13.4 16 14 +90 mL H₂O15.4 13.7 16 13.5 +95 mL H₂O 14.8 13.1 14.1 12.2 +100 mL H₂O 14.3 12.313.5 11.9 +105 mL H₂O 13.6 12.5 14.4 11.1 +110 mL H₂O 13.2 11.6 12.611.4 +115 mL H₂O 12.9 11.8 12.6 10.2 +120 mL H₂O 12.5 11.2 12.1 10.2+125 mL H₂O 12 10.8 15.5 9.7 +130 mL H₂O 11.9 10.4 12.7 9.3 +135 mL H₂O11.6 10.5 11.3 9.3 +140 mL H₂O 11.5 9.6 10.8 9.2 +145 mL H₂O 11.1 10.410.7 8.7 +150 mL H₂O 10.8 10 13 9 +155 mL H₂O 10.7 9.2 10.1 8.3 +160 mLH₂O 10.3 9.2 9.8 8.2 +165 mL H₂O 10 10 9.3 8.1 +170 mL H₂O 9.8 8.6 9.37.9 +175 mL H₂O 9.5 8.6 9.2 7.7 +180 mL H₂O 9.2 8.2 10.5 7.8 +185 mL H₂O9 8 8.5 8.2 +190 mL H₂O 9.4 8.3 8.4 7 +195 mL H₂O 9.4 7.6 8.2 7 +200 mLH₂O 9 7.8 8.5 6.9 +205 mL H₂O 8.4 7.8 7.8 6.5 +210 mL H₂O 8.4 7.3 7.76.5 +215 mL H₂O 8.1 7 7.5 6.3 +220 mL H₂O 8.8 7 7.8 6 +225 mL H₂O 8.36.9 7.6 6 +230 mL H₂O 8.1 6.7 7.2 5.9

The experimental findings show that the turbidity profile of formulationaccording to the comparative sample C-1 is comparable to the turbidityprofiles of the formulations according to the inventive examples 1-1,1-2 and 1-3, meaning that the presence of compound (I′a) hardly has aninfluence on the ability to (micro)emulsify of these formulations

Example 6

The following SMEDDS (self-microemulsifying drug delivery system)formulation was prepared:

Solutol ® HS 15 60% (w/w) Miglyol 812 20% (w/w) Ethanol (abs.) 20% (w/w)

From the SMEDDS formulation and appropriate amounts of compound (I′b),solutions were prepared, that were then put into hard gelatin capsules.According to the following composition capsules of two dosages wereprepared (50 μg and 400 μg):

TABLE 22 % (m/m), Amount % (m/m), Amount Dosage per capsule Dosage percapsule Ingredient 50 μg [mg] 400 μg [mg] Formulation 99.986 349.9599.886 349.6 SMEDDS Compound (I′b) 0.014 0.05 0.114 0.4 Total 100.0350.0 100.0 350.0

Two batches of about 1000 of these hard gelatin capsules weremanufactured for each of both dosages and packaged in brown glasses withscrew caps. The SMEDDS formulations were put into empty hard gelatincapsules (size 0) and subjected to stability testing studies at 25°C./60% relative humidity (RH) (long-term storage conditions) and 40°C./75% RH (accelerated storage conditions). Samples were charged instability chambers with humidity and temperature control. They werewithdrawn at specified intervals for analysis over a period of 6 months.Drug content of the capsules was analyzed using a previously developedand validated stability-indicating HPLC method. Besides the chemicalstability of the drug, the dissolution profile of the dosage form wasalso studied.

The testing results revealed that all measured parameters (unity of thedrug content, the drug's purity, release of the drug) met the demands ofthe ICH and FDA guidelines. The determined content of the decompositionproduct6′-fluoro-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohex-3-ene-1,1′-pyrano[3,4-b]indole]after storage at 40° C. and 75% rh was for dosage 50 μg 0.16% after 1month, 0.25% after 3 months and 0.42% after 6 months; and for dosage 400μg 0.09% after 1 month, 0.12% after 3 months and 0.25% after 6 months.

Example 7

Clinical studies were conducted to determine the analgesic efficacy andtolerability of single doses of the compound according to formula (I′b)(200 μg, 400 μg and 600 μg; hemicitrate oral solution of compound (I′b)in Macrogol 400; all dosages relative to the free base of the drug)compared to that of morphine (60 mg, controlled-released form) andplacebo in patients with acute post-operative pain following orthopedicsurgery (bunionectomy).

For this purpose, 258 patients of either sex were included in arandomized, placebo-controlled, double-blind clinical trial in parallelgroups. Treatment groups were well-balanced with respect to demographicsand baseline characteristics with a slight imbalance in baseline painand ethnicity.

After surgery, all patients were initially treated with localpost-operative anesthesia via a popliteal block. Due to differentkinetics of the compound according to formula (I′b) and morphine, thepatients were then treated with either one of the two drugs or withplacebo at slightly different times:

One hour before the popliteal block was stopped, patients wererandomized and part of them were dosed with a single dose of thecompound according to formula (I′b) (200 μg, 400 μg or 600 μg) orplacebo, while the others received morphine or placebo 2 hours after thepopliteal block had been stopped.

The primary efficacy assessment endpoint was the absolute pain intensityover a 24 hour period. Pain intensity was measured using an 11-pointnumerical rating scale (NRS). At each time point, patients wereinstructed to evaluate their current pain intensity relative to an11-point numerical rating scale. A score of zero represented no pain anda score of 10 represented worst possible pain. Missing scheduled painassessments for the patients were imputed with the last observationcarried forward (LOCF). The resulting averaged NRS values over the 24hour period are depicted in FIG. 1.

Sum of pain intensity differences over different time periods wereanalyzed using an analysis of covariance (ANCOVA) model with factors fortreatment and site and baseline pain intensity score (using the painintensity NPRS score). Only subjects with non-missing baseline painintensity were included. A summary of the analysis for the 2 to 10 hourperiod is presented in Table 23. The resulting p-values are summarizedin Table 24.

TABLE 23 LS mean n LS mean SE Δplacebo SE P-value Placebo 45 49.13 2.85compound (I′b) 52 46.05 2.78 −3.08 3.49 0.3776 200 μg compound (I′b) 4735.28 2.81 −13.85 3.57 0.0001 400 μg compound (I′b) 55 35.15 2.67 −13.983.45 <0.0001 600 μg morphine, 49 42.01 2.83 −7.12 3.54 0.0454controlled- release 60 mg LS mean: least squares means; SE: statisticalerror

The resulting p-values of the analysis of all time windows evaluated aresummarized in Table 24.

TABLE 24 p-values (sum of pain intensity differences) 2-6 h 2-10 h 2-12h 2-14 h 2-18 h 2-24 h compound (I′b) 0.4514 0.3776 0.3387 0.3427 0.32050.2923 200 μg compound (I′b) 0.0009 0.0001 <0.0001 0.0001 0.0005 0.0008400 μg compound (I′b) 0.0009 <0.0001 <0.0001 <0.0001 <0.0001 0.0001 600μg morphine, 0.4664 0.0454 0.0084 0.0036 0.0014 0.0005 controlled-release 60 mg

Accordingly, on the primary parameter, a statistically significantdifference was observed between groups that had received a 400 μg or 600μg dose of compound (I′b) and placebo groups, whereas no statisticallysignificant difference was observed for groups that had received a 200μg dose of compound (I′b).

Tables 25 and 26 summarize the treatment emergent adverse events(TEAE(s)) experienced by the five treatment groups.

TABLE 25 compound (I′b) compound (I′b) compound (I′b) morphine Placebo200 μg 400 μg 600 μg 60 mg subjects with TEAE(s) (n (%)) 32 (68.1) 37(67.3) 38 (77.6) 48 (84.2) 46 (92.0) related (n (%)) 17 (36.2) 24 (43.6)32 (65.3) 43 (75.4) 42 (84.0) serious (n (%)) 1 (2.1) 0 0 0 0 totalnumber of TEAE's(n) 74 75  125  198  144  related (n (%)) 32 (43.2) 37(49.3) 74 (59.2) 146 (73.7) 99 (68.8) subjects with SAE's 1 (2.1) 0 0 00 deaths  0 0 0 0 0 TEAE: treatment emergent adverse event; SAE: seriousadverse event

TABLE 26 compound compound compound Pla- (I′b) (I′b) (I′b) morphine cebo200 μg 400 μg 600 μg 60 mg Nausea 17.0 29.1 49.0 64.9 66.0 Vomiting 2.19.1 20.4 49.1 40.0 Dizziness 6.4 20.0 22.4 26.3 24.0 Somnolence 2.1 1.810.2 14.0 16.0 ASAT increased 2.1 1.8 6.1 1.8 2.0 Hot flush 0 1.8 4.17.0 4.0 Pruritus 0 0 6.1 3.5 2.0 Hyperhidrosis 0 0 0 5.3 6.0 100% =total number of subjects in corresponding treatment group; ASAT:aspartate aminotransferase

It becomes evident from Tables 25 and 26 that all four active treatmentswere well tolerated under these circumstances and the adverse eventsthat showed up most frequently are in line with what can be expectedfrom μ-opioid receptor agonists. For the patient group that had beentreated with compound (I′b), the incidence of adverse events increasedwith the dose, and at a dose of 600 μg the incidence of adverse eventswas comparable to that of the morphine patient group, although the 400μg dose was already comparable in efficacy.

Example 8

Clinical studies were conducted to determine the bioavailability of aliquid filled capsule formulation containing compound (I′b) in a dosestrength of 400 μg compared to a hemicitrate oral solution of compound(I′b) (400 μg, 400 μg/mL oral solution) in a Macrogol 400 formulationafter single oral administration. 24 healthy white male subjects wereincluded in a randomized, open-label, 3-way crossover, single-centerclinical trial. The main pharmacokinetic parameters were AUC_(0-t),AUC_(0-72h) and C_(max).

The results are summarized in Tables 27 to 29.

TABLE 27 pharmaco- kinetic C_(max) AUC_(0-72 h) AUC_(0-t) parametert_(max)* [h] [pg/mL] [h · pg/mL] [h · pg/mL] 400 μg/mL 6.00 127 ± 52.42771 ± 1376 3843 ± 2081 oral solution (2.08; 6.00) (41.2%) (49.7%)(54.1%) 400 μg 6.00 131 ± 58.1 2814 ± 1637 3733 ± 2265 capsule (2.08;10.0) (44.2%) (58.2%) (60.7%) N = 24; The table presents the arithmeticmeans +/− the standard deviation (coefficient of variation).

TABLE 28 comparison capsules/oral solution C_(max) AUC_(0-72 h)AUC_(0-t) 400 μg capsule/ 105% 105% 100% 400 μg/mL oral solution(94.4%-116%) (96%-116%) (91.0%-111%)

TABLE 29 total number Subjects with TEAE(s) TEAE(S) of subjects (N) n %e 400 μg capsule 24 14 58.3 32 400 μg/mL oral 24 18 75.0 43 solution n:number of subjects with at least one TEAE (treatment emergent adverseevent); %: corresponding ratio of subjects experiencing TEAE(s); e:number of TEAE(s)

Accordingly, the relative bioavailability of the 400 μg capsule and 400μg/mL oral solution based on AUC_(0-72h) was 105%, with 90%-Cl withinthe 80% to 125% range conventionally used for assessing bioequivalence.

Single oral dose administrations of 400 μg of compound (I′b) were safeand well tolerated independent from the galenic formulation. No seriousadverse events occurred.

Prophetic Examples

Prophetic examples of pharmaceutical dosage forms according to theinvention are provided below. Their compositions are intended to beexemplary and it should be understood that the ingredients, the amountthereof and the procedure to obtain the dosage form may be varied.

According to example 6, hard gelatin capsules containing compound (I′b)in a dosage of, for instance, 40 or 400 μg, can also be produced bymeans of the following SMEDDS formulations:

Ingredients [%] PE-A1 PE-A2 PE-A3 PE-A4 PE-A5 Solutol ® HS 15 10 17.5 2532.5 40 Miglyol 812 60 55 50 40 30 Ethanol (abs.) 30 27.5 25 27.5 30PE-A6 PE-A7 PE-A8 PE-A9 PE-A10 Solutol ® HS 15 45 50 65 80 87.5 Miglyol812 27.5 25 20 15 10 Ethanol (abs.) 27.5 25 15 5 2.5 Ingredients [%]PE-B1 PE-B2 PE-B3 PE-B4 PE-B5 Gelucire 44/14 50 55 60 62.5 65 Labrasol25 22.5 20 20 20 Capryol 90 25 22.5 20 17.5 15 Ingredients [%] PE-B6PE-B7 PE-B8 PE-B9 PE-B10 Gelucire 44/14 67.5 70 75 80 82.5 Labrasol 17.515 12.5 10 7.5 Capryol 90 15 15 12.5 10 10 Ingredients [%] PE-C1 PE-C2PE-C3 PE-C4 PE-C5 Cremophor RH 40 5 12.5 20 25 30 Peceol 15 17.5 20 2020 Miglyol 812 80 70 60 55 50 Ingredients [%] PE-C6 PE-C7 PE-C8 PE-C9PE-C10 Cremophor RH 40 35 40 47.5 55 60 Peceol 20 20 17.5 15 12.5Miglyol 812 45 40 35 30 27.5

General Procedure for Preparing the Solid Solution According to theInvention

Active pharmaceutical ingredient (API), i.e. the pharmacologicallyactive agent according to general formula (I), and a polymer weredispersed in dichloromethane in a flask. In some cases, a surfactant wasadded. The flask was heated and subjected to ultrasound in order todissolve the ingredients properly. Where applicable, the solution wasfiltered through a sintered glass filter in order to remove traces ofundissolved material. The solvent was evaporated by means of a rotaryevaporator at a temperature of 60° C. The solid residue was furtherdried under high vacuum overnight. The dried material was transferred toa sealed glass vial for the analysis for amorphous contents by usingXRPD and DSC. The dissolution behavior was analyzed in 0.1N HCl.

Example 9

Following the general procedure, solid solutions having the followingcompositions were prepared:

weight ratio content Ex. API polymer API:polymer surfactant surfactant1-A + — — — — 1-B + Kollidon 90 1:4 — — 1-C + Kollidon 90 1:4 Pluronic 5wt.-% F68 1-D + Kollidon VA 64 1:5 Tween 80 5 wt.-% 1-E + Kollidon VA 64 1:19 Tween 80 5 wt.-%

FIG. 2 shows the release profile of the API. The X-Axis refers to thetime in minutes and the Y-Axis refers to the amount of dissolved API inpercent in relation to the whole amount API originally contained in thedosage form.

It becomes evident from FIG. 2 that the solid solution containingKollidon VA64/Tween 80 in a ratio of 1:19 of the API and the polymer(example 1-E) showed a substantially higher dissolution rate than any ofthe other formulations (examples 1-A to 1-D). Nearly 90% of the API wasdissolved in the first 30 minutes. Pluronic F68 to the formulation withKollidon 90 (1:4) resulted in a substantial decrease of the dissolutionrate. Pluronic F68 is a difunctional block copolymer surfactantterminating in primary hydroxyl groups and having a HLB value of >24.

Example 10

Following the general procedure and in analogy to example 1, solidsolutions having the following compositions were prepared:

weight ratio content Ex. API polymer API:polymer surfactant surfactant2-A + — — — — 2-B + Kollidon VA64 1:19 — — 2-C + Kollidon VA64 1:19Tween 80 5 wt.-%

FIG. 3 shows the release profile of the API. The X-Axis refers to thetime in minutes and the Y-Axis refers to the amount of dissolved API inpercent in relation to the whole amount API originally contained in thedosage form.

It becomes evident from FIG. 3 that the formulation containing Tween 80provided a faster release with a high extent of dissolution, while inthe absence of the surfactant the dissolution rate was reduced; in theabsence of surfactant (example 2-B), the overall extent of dissolutionwas only 55% compared to the formulation containing Tween 80 (example2-C).

Example 11

The storage stability of a solid solution was tested under variousconditions and analyzed by using XRPD. The solid solution was preparedin accordance with examples 1 and 2 and had the following composition:

weight ratio content Ex. API polymer API:polymer surfactant surfactant3 + Kollidon VA64 1:19 Tween 80 4 wt.-%

Unit doses of the blended formulation were filled into size 0 hardgelatin capsules. The encapsulated formulations were stored at 25° C.and 60% relative humidity (RH) at 30° C. and 65% relative humidity,respectively. After predetermined time periods of 1, 2, and 4 weeks, thecapsules were removed from the storage and analyzed.

The solid solution of the API, especially the formulation with API:V64in a ratio of 1:19, revealed to be physically stable over a time periodof 4 weeks at 25° C. and 30° C. demonstrated via XRPD.

FIG. 4 shows the XRPD result of the API solid solution at time zero.

FIGS. 5 and 6 show the result after 4 weeks of storage at 25° C. and 60%relative humidity and at 30° C. and 65% relative humidity, respectively.

It is clear from FIGS. 4 to 6 that the drug product has amorphous or atleast semi-amorphous nature.

Example 12

Clinical studies were conducted to determine the analgesic efficacy andtolerability of single doses of the compound according to formula (I′b)(200 μg, 400 μg and 600 μg, based on the amount of the free base;hemicitrate oral solution of compound (I′b) in Macrogol 400) compared tothat of morphine (60 mg, controlled-released form) and placebo inpatients with acute post-operative pain following orthopedic surgery(bunionectomy).

For this purpose, 258 patients of either sex were included in arandomized, placebo-controlled, double-blind clinical trial in parallelgroups. Treatment groups were well-balanced with respect to demographicsand baseline characteristics with a slight imbalance in baseline painand ethnicity.

After surgery, all patients were initially treated with localpost-operative anesthesia via a popliteal block. Due to differentkinetics of the compound according to formula (I′b) and morphine, thepatients were then treated with either one of the two drugs or withplacebo at slightly different times:

One hour before the popliteal block was stopped, patients wererandomized and part of them were dosed with a single dose of thecompound according to formula (I′b) (200 μg, 400 μg or 600 μg) orplacebo, while the others received morphine or placebo 2 hours after thepopliteal block had been stopped.

The primary efficacy assessment endpoint was the absolute pain intensityover a 24 hour period. Pain intensity was measured using an 11-pointnumerical rating scale (NRS). At each time point, patients wereinstructed to evaluate their current pain intensity relative to an11-point numerical rating scale. A score of zero represented no pain anda score of 10 represented worst possible pain. Missing scheduled painassessments for the patients were imputed with the last observationcarried forward (LOCF). The resulting averaged NRS values over the 24hour period are depicted in FIG. 6.

Sum of pain intensity differences over different time periods wereanalyzed using an analysis of covariance (ANCOVA) model with factors fortreatment and site and baseline pain intensity score (using the painintensity NPRS score). Only subjects with non-missing baseline painintensity were included. A summary of the analysis for the 2 to 10 hourperiod is presented in the following Table 30:

TABLE 30 LS mean n LS mean SE Δplacebo SE P-value placebo 45 49.13 2.85compound (I′b) 52 46.05 2.78 −3.08 3.49 0.3776 200 μg compound (I′b) 4735.28 2.81 −13.85 3.57 0.0001 400 μg compound (I′b) 55 35.15 2.67 −13.983.45 <0.0001 600 μg morphine, 49 42.01 2.83 −7.12 3.54 0.0454controlled- release 60 mg LS mean: least squares means; SE: statisticalerror

The resulting p-values are summarized in the following Table 31:

TABLE 31 p-values (sum of pain intensity differences) 2-6 h 2-10 h 2-12h 2-14 h 2-18 h 2-24 h compound (I′b) 0.4514 0.3776 0.3387 0.3427 0.32050.2923 200 μg compound (I′b) 0.0009 0.0001 <0.0001 0.0001 0.0005 0.0008400 μg compound (I′b) 0.0009 <0.0001 <0.0001 <0.0001 <0.0001 0.0001 600μg morphine, 0.4664 0.0454 0.0084 0.0036 0.0014 0.0005 controlled-release 60 mg

Accordingly, on the primary parameter, a statistically significantdifference was observed between groups that had received a 400 μg or 600μg dose of compound (I′b) and placebo groups, whereas no statisticallysignificant difference was observed for groups that had received a 200μg dose of compound (I′b).

The following Tables 32 and 33 summarize the treatment emergent adverseevents (TEAE(s)) experienced by the five treatment groups.

TABLE 32 compound (I′b) compound (I′b) compound (I′b) morphine Placebo200 μg 400 μg 600 μg 60 mg subjects with TEAE(s) (n (%)) 32 (68.1) 37(67.3) 38 (77.6) 48 (84.2) 46 (92.0) related (n (%)) 17 (36.2) 24 (43.6)32 (65.3) 43 (75.4) 42 (84.0) serious (n (%)) 1 (2.1) 0 0 0 0 totalnumber of TEAE's (n) 74 75  125  198  144  related (n (%)) 32 (43.2) 37(49.3) 74 (59.2) 146 (73.7) 99 (68.8) subjects with SAE's 1 (2.1) 0 0 00 Deaths  0 0 0 0 0 TEAE: treatment emergent adverse event; SAE: seriousadverse event

TABLE 33 compound compound compound Pla- (I′b) (I′b) (I′b) morphine cebo200 μg 400 μg 600 μg 60 mg Nausea 17.0 29.1 49.0 64.9 66.0 Vomiting 2.19.1 20.4 49.1 40.0 Dizziness 6.4 20.0 22.4 26.3 24.0 Somnolence 2.1 1.810.2 14.0 16.0 ASAT increased 2.1 1.8 6.1 1.8 2.0 Hot flush 0 1.8 4.17.0 4.0 Pruritus 0 0 6.1 3.5 2.0 Hyperhidrosis 0 0 0 5.3 6.0 100% =total number of subjects in corresponding treatment group; ASAT:aspartate aminotransferase

It becomes evident from the foregoing Tables 32 and 33 that all fouractive treatments were well tolerated under these circumstances and theadverse events that showed up most frequently are in line with what canbe expected from μ-opioid receptor agonists. For the patient group thathad been treated with compound (I′b), the incidence of adverse eventsincreased with the dose, and at a dose of 600 μg the incidence ofadverse events was comparable to that of the morphine patient group.

Prophetic Examples

Prophetic examples of pharmaceutical dosage forms according to theinvention are provided below. Their compositions are intended to beexemplary and it should be understood that the ingredients, the amountthereof and the procedure to obtain the dosage form may be varied.

In analogy to examples 1, 2 and 3, the following compositions (solidsolutions) can be prepared in accordance with the general procedure:

Prophetic Example 1

weight ratio content Ex. API polymer API:polymer surfactant surfactantP1-1-A-1 + Kollidon 90 1:8  Tween 80 1 wt.-% P1-1-A-2 + Kollidon 90 1:8 Tween 80 2.5 wt.-% P1-1-A-3 + Kollidon 90 1:8  Tween 80 5 wt.-%P1-1-A-4 + Kollidon 90 1:8  Tween 80 7.5 wt.-% P1-1-A-5 + Kollidon 901:8  Tween 80 10 wt.-% P1-1-B-1 + Kollidon 90 1:12 Tween 80 1 wt.-%P1-1-B-2 + Kollidon 90 1:12 Tween 80 2.5 wt.-% P1-1-B-3 + Kollidon 901:12 Tween 80 5 wt.-% P1-1-B-4 + Kollidon 90 1:12 Tween 80 7.5 wt.-%P1-1-B-5 + Kollidon 90 1:12 Tween 80 10 wt.-% P1-1-C-1 + Kollidon 901:16 Tween 80 1 wt.-% P1-1-C-2 + Kollidon 90 1:16 Tween 80 2.5 wt.-%P1-1-C-3 + Kollidon 90 1:16 Tween 80 5 wt.-% P1-1-C-4 + Kollidon 90 1:16Tween 80 7.5 wt.-% P1-1-C-5 + Kollidon 90 1:16 Tween 80 10 wt.-%P1-1-D-1 + Kollidon 90 1:20 Tween 80 1 wt.-% P1-1-D-2 + Kollidon 90 1:20Tween 80 2.5 wt.-% P1-1-D-3 + Kollidon 90 1:20 Tween 80 5 wt.-%P1-1-D-4 + Kollidon 90 1:20 Tween 80 7.5 wt.-% P1-1-D-5 + Kollidon 901:20 Tween 80 10 wt.-% P1-1-E-1 + Kollidon 90 1:24 Tween 80 1 wt.-%P1-1-E-2 + Kollidon 90 1:24 Tween 80 2.5 wt.-% P1-1-E-3 + Kollidon 901:24 Tween 80 5 wt.-% P1-1-E-4 + Kollidon 90 1:24 Tween 80 7.5 wt.-%P1-1-E-5 + Kollidon 90 1:24 Tween 80 10 wt.-% P1-2-A-1 + Kollidon 901:8  Solutol HS 15 1 wt.-% P1-2-A-2 + Kollidon 90 1:8  Solutol HS 15 2.5wt.-% P1-2-A-3 + Kollidon 90 1:8  Solutol HS 15 5 wt.-% P1-2-A-4 +Kollidon 90 1:8  Solutol HS 15 7.5 wt.-% P1-2-A-5 + Kollidon 90 1:8 Solutol HS 15 10 wt.-% P1-2-B-1 + Kollidon 90 1:12 Solutol HS 15 1 wt.-%P1-2-B-2 + Kollidon 90 1:12 Solutol HS 15 2.5 wt.-% P1-2-B-3 + Kollidon90 1:12 Solutol HS 15 5 wt.-% P1-2-B-4 + Kollidon 90 1:12 Solutol HS 157.5 wt.-% P1-2-B-5 + Kollidon 90 1:12 Solutol HS 15 10 wt.-% P1-2-C-1 +Kollidon 90 1:16 Solutol HS 15 1 wt.-% P1-2-C-2 + Kollidon 90 1:16Solutol HS 15 2.5 wt.-% P1-2-C-3 + Kollidon 90 1:16 Solutol HS 15 5wt.-% P1-2-C-4 + Kollidon 90 1:16 Solutol HS 15 7.5 wt.-% P1-2-C-5 +Kollidon 90 1:16 Solutol HS 15 10 wt.-% P1-2-D-1 + Kollidon 90 1:20Solutol HS 15 1 wt.-% P1-2-D-2 + Kollidon 90 1:20 Solutol HS 15 2.5wt.-% P1-2-D-3 + Kollidon 90 1:20 Solutol HS 15 5 wt.-% P1-2-D-4 +Kollidon 90 1:20 Solutol HS 15 7.5 wt.-% P1-2-D-5 + Kollidon 90 1:20Solutol HS 15 10 wt.-% P1-2-E-1 + Kollidon 90 1:24 Solutol HS 15 1 wt.-%P1-2-E-2 + Kollidon 90 1:24 Solutol HS 15 2.5 wt.-% P1-2-E-3 + Kollidon90 1:24 Solutol HS 15 5 wt.-% P1-2-E-4 + Kollidon 90 1:24 Solutol HS 157.5 wt.-% P1-2-E-5 + Kollidon 90 1:24 Solutol HS 15 10 wt.-% P1-3-A-1 +Kollidon 90 1:8  Tween 60 1 wt.-% P1-3-A-2 + Kollidon 90 1:8  Tween 602.5 wt.-% P1-3-A-3 + Kollidon 90 1:8  Tween 60 5 wt.-% P1-3-A-4 +Kollidon 90 1:8  Tween 60 7.5 wt.-% P1-3-A-5 + Kollidon 90 1:8  Tween 6010 wt.-% P1-3-B-1 + Kollidon 90 1:12 Tween 60 1 wt.-% P1-3-B-2 +Kollidon 90 1:12 Tween 60 2.5 wt.-% P1-3-B-3 + Kollidon 90 1:12 Tween 605 wt.-% P1-3-B-4 + Kollidon 90 1:12 Tween 60 7.5 wt.-% P1-3-B-5 +Kollidon 90 1:12 Tween 60 10 wt.-% P1-3-C-1 + Kollidon 90 1:16 Tween 601 wt.-% P1-3-C-2 + Kollidon 90 1:16 Tween 60 2.5 wt.-% P1-3-C-3 +Kollidon 90 1:16 Tween 60 5 wt.-% P1-3-C-4 + Kollidon 90 1:16 Tween 607.5 wt.-% P1-3-C-5 + Kollidon 90 1:16 Tween 60 10 wt.-% P1-3-D-1 +Kollidon 90 1:20 Tween 60 1 wt.-% P1-3-D-2 + Kollidon 90 1:20 Tween 602.5 wt.-% P1-3-D-3 + Kollidon 90 1:20 Tween 60 5 wt.-% P1-3-D-4 +Kollidon 90 1:20 Tween 60 7.5 wt.-% P1-3-D-5 + Kollidon 90 1:20 Tween 6010 wt.-% P1-3-E-1 + Kollidon 90 1:24 Tween 60 1 wt.-% P1-3-E-2 +Kollidon 90 1:24 Tween 60 2.5 wt.-% P1-3-E-3 + Kollidon 90 1:24 Tween 605 wt.-% P1-3-E-4 + Kollidon 90 1:24 Tween 60 7.5 wt.-% P1-3-E-5 +Kollidon 90 1:24 Tween 60 10 wt.-% P1-4-A-1 + Kollidon 90 1:8  Myrj 51 1wt.-% P1-4-A-2 + Kollidon 90 1:8  Myrj 51 2.5 wt.-% P1-4-A-3 + Kollidon90 1:8  Myrj 51 5 wt.-% P1-4-A-4 + Kollidon 90 1:8  Myrj 51 7.5 wt.-%P1-4-A-5 + Kollidon 90 1:8  Myrj 51 10 wt.-% P1-4-B-1 + Kollidon 90 1:12Myrj 51 1 wt.-% P1-4-B-2 + Kollidon 90 1:12 Myrj 51 2.5 wt.-% P1-4-B-3 +Kollidon 90 1:12 Myrj 51 5 wt.-% P1-4-B-4 + Kollidon 90 1:12 Myrj 51 7.5wt.-% P1-4-B-5 + Kollidon 90 1:12 Myrj 51 10 wt.-% P1-4-C-1 + Kollidon90 1:16 Myrj 51 1 wt.-% P1-4-C-2 + Kollidon 90 1:16 Myrj 51 2.5 wt.-%P1-4-C-3 + Kollidon 90 1:16 Myrj 51 5 wt.-% P1-4-C-4 + Kollidon 90 1:16Myrj 51 7.5 wt.-% P1-4-C-5 + Kollidon 90 1:16 Myrj 51 10 wt.-%P1-4-D-1 + Kollidon 90 1:20 Myrj 51 1 wt.-% P1-4-D-2 + Kollidon 90 1:20Myrj 51 2.5 wt.-% P1-4-D-3 + Kollidon 90 1:20 Myrj 51 5 wt.-% P1-4-D-4 +Kollidon 90 1:20 Myrj 51 7.5 wt.-% P1-4-D-5 + Kollidon 90 1:20 Myrj 5110 wt.-% P1-4-E-1 + Kollidon 90 1:24 Myrj 51 1 wt.-% P1-4-E-2 + Kollidon90 1:24 Myrj 51 2.5 wt.-% P1-4-E-3 + Kollidon 90 1:24 Myrj 51 5 wt.-%P1-4-E-4 + Kollidon 90 1:24 Myrj 51 7.5 wt.-% P1-4-E-5 + Kollidon 901:24 Myrj 51 10 wt.-% P1-5-A-1 + Kollidon 90 1:8  Brij 98 1 wt.-%P1-5-A-2 + Kollidon 90 1:8  Brij 98 2.5 wt.-% P1-5-A-3 + Kollidon 901:8  Brij 98 5 wt.-% P1-5-A-4 + Kollidon 90 1:8  Brij 98 7.5 wt.-%P1-5-A-5 + Kollidon 90 1:8  Brij 98 10 wt.-% P1-5-B-1 + Kollidon 90 1:12Brij 98 1 wt.-% P1-5-B-2 + Kollidon 90 1:12 Brij 98 2.5 wt.-% P1-5-B-3 +Kollidon 90 1:12 Brij 98 5 wt.-% P1-5-B-4 + Kollidon 90 1:12 Brij 98 7.5wt.-% P1-5-B-5 + Kollidon 90 1:12 Brij 98 10 wt.-% P1-5-C-1 + Kollidon90 1:16 Brij 98 1 wt.-% P1-5-C-2 + Kollidon 90 1:16 Brij 98 2.5 wt.-%P1-5-C-3 + Kollidon 90 1:16 Brij 98 5 wt.-% P1-5-C-4 + Kollidon 90 1:16Brij 98 7.5 wt.-% P1-5-C-5 + Kollidon 90 1:16 Brij 98 10 wt.-%P1-5-D-1 + Kollidon 90 1:20 Brij 98 1 wt.-% P1-5-D-2 + Kollidon 90 1:20Brij 98 2.5 wt.-% P1-5-D-3 + Kollidon 90 1:20 Brij 98 5 wt.-% P1-5-D-4 +Kollidon 90 1:20 Brij 98 7.5 wt.-% P1-5-D-5 + Kollidon 90 1:20 Brij 9810 wt.-% P1-5-E-1 + Kollidon 90 1:24 Brij 98 1 wt.-% P1-5-E-2 + Kollidon90 1:24 Brij 98 2.5 wt.-% P1-5-E-3 + Kollidon 90 1:24 Brij 98 5 wt.-%P1-5-E-4 + Kollidon 90 1:24 Brij 98 7.5 wt.-% P1-5-E-5 + Kollidon 901:24 Brij 98 10 wt.-%

Prophetic Example 2

weight ratio content Ex. API polymer API:polymer surfactant surfactantP2-1-A-1 + Kollidon VA64 1:8  Tween 80 1 wt.-% P2-1-A-2 + Kollidon VA641:8  Tween 80 2.5 wt.-% P2-1-A-3 + Kollidon VA64 1:8  Tween 80 5 wt.-%P2-1-A-4 + Kollidon VA64 1:8  Tween 80 7.5 wt.-% P2-1-A-5 + KollidonVA64 1:8  Tween 80 10 wt.-% P2-1-B-1 + Kollidon VA64 1:12 Tween 80 1wt.-% P2-1-B-2 + Kollidon VA64 1:12 Tween 80 2.5 wt.-% P2-1-B-3 +Kollidon VA64 1:12 Tween 80 5 wt.-% P2-1-B-4 + Kollidon VA64 1:12 Tween80 7.5 wt.-% P2-1-B-5 + Kollidon VA64 1:12 Tween 80 10 wt.-% P2-1-C-1 +Kollidon VA64 1:16 Tween 80 1 wt.-% P2-1-C-2 + Kollidon VA64 1:16 Tween80 2.5 wt.-% P2-1-C-3 + Kollidon VA64 1:16 Tween 80 5 wt.-% P2-1-C-4 +Kollidon VA64 1:16 Tween 80 7.5 wt.-% P2-1-C-5 + Kollidon VA64 1:16Tween 80 10 wt.-% P2-1-D-1 + Kollidon VA64 1:20 Tween 80 1 wt.-%P2-1-D-2 + Kollidon VA64 1:20 Tween 80 2.5 wt.-% P2-1-D-3 + KollidonVA64 1:20 Tween 80 5 wt.-% P2-1-D-4 + Kollidon VA64 1:20 Tween 80 7.5wt.-% P2-1-D-5 + Kollidon VA64 1:20 Tween 80 10 wt.-% P2-1-E-1 +Kollidon VA64 1:24 Tween 80 1 wt.-% P2-1-E-2 + Kollidon VA64 1:24 Tween80 2.5 wt.-% P2-1-E-3 + Kollidon VA64 1:24 Tween 80 5 wt.-% P2-1-E-4 +Kollidon VA64 1:24 Tween 80 7.5 wt.-% P2-1-E-5 + Kollidon VA64 1:24Tween 80 10 wt.-% P2-2-A-1 + Kollidon VA64 1:8  Solutol HS 15 1 wt.-%P2-2-A-2 + Kollidon VA64 1:8  Solutol HS 15 2.5 wt.-% P2-2-A-3 +Kollidon VA64 1:8  Solutol HS 15 5 wt.-% P2-2-A-4 + Kollidon VA64 1:8 Solutol HS 15 7.5 wt.-% P2-2-A-5 + Kollidon VA64 1:8  Solutol HS 15 10wt.-% P2-2-B-1 + Kollidon VA64 1:12 Solutol HS 15 1 wt.-% P2-2-B-2 +Kollidon VA64 1:12 Solutol HS 15 2.5 wt.-% P2-2-B-3 + Kollidon VA64 1:12Solutol HS 15 5 wt.-% P2-2-B-4 + Kollidon VA64 1:12 Solutol HS 15 7.5wt.-% P2-2-B-5 + Kollidon VA64 1:12 Solutol HS 15 10 wt.-% P2-2-C-1 +Kollidon VA64 1:16 Solutol HS 15 1 wt.-% P2-2-C-2 + Kollidon VA64 1:16Solutol HS 15 2.5 wt.-% P2-2-C-3 + Kollidon VA64 1:16 Solutol HS 15 5wt.-% P2-2-C-4 + Kollidon VA64 1:16 Solutol HS 15 7.5 wt.-% P2-2-C-5 +Kollidon VA64 1:16 Solutol HS 15 10 wt.-% P2-2-D-1 + Kollidon VA64 1:20Solutol HS 15 1 wt.-% P2-2-D-2 + Kollidon VA64 1:20 Solutol HS 15 2.5wt.-% P2-2-D-3 + Kollidon VA64 1:20 Solutol HS 15 5 wt.-% P2-2-D-4 +Kollidon VA64 1:20 Solutol HS 15 7.5 wt.-% P2-2-D-5 + Kollidon VA64 1:20Solutol HS 15 10 wt.-% P2-2-E-1 + Kollidon VA64 1:24 Solutol HS 15 1wt.-% P2-2-E-2 + Kollidon VA64 1:24 Solutol HS 15 2.5 wt.-% P2-2-E-3 +Kollidon VA64 1:24 Solutol HS 15 5 wt.-% P2-2-E-4 + Kollidon VA64 1:24Solutol HS 15 7.5 wt.-% P2-2-E-5 + Kollidon VA64 1:24 Solutol HS 15 10wt.-% P2-3-A-1 + Kollidon VA64 1:8  Pluronic F127 1 wt.-% P2-3-A-2 +Kollidon VA64 1:8  Pluronic F127 2.5 wt.-% P2-3-A-3 + Kollidon VA64 1:8 Pluronic F127 5 wt.-% P2-3-A-4 + Kollidon VA64 1:8  Pluronic F127 7.5wt.-% P2-3-A-5 + Kollidon VA64 1:8  Pluronic F127 10 wt.-% P2-3-B-1 +Kollidon VA64 1:12 Pluronic F127 1 wt.-% P2-3-B-2 + Kollidon VA64 1:12Pluronic F127 2.5 wt.-% P2-3-B-3 + Kollidon VA64 1:12 Pluronic F127 5wt.-% P2-3-B-4 + Kollidon VA64 1:12 Pluronic F127 7.5 wt.-% P2-3-B-5 +Kollidon VA64 1:12 Pluronic F127 10 wt.-% P2-3-C-1 + Kollidon VA64 1:16Pluronic F127 1 wt.-% P2-3-C-2 + Kollidon VA64 1:16 Pluronic F127 2.5wt.-% P2-3-C-3 + Kollidon VA64 1:16 Pluronic F127 5 wt.-% P2-3-C-4 +Kollidon VA64 1:16 Pluronic F127 7.5 wt.-% P2-3-C-5 + Kollidon VA64 1:16Pluronic F127 10 wt.-% P2-3-D-1 + Kollidon VA64 1:20 Pluronic F127 1wt.-% P2-3-D-2 + Kollidon VA64 1:20 Pluronic F127 2.5 wt.-% P2-3-D-3 +Kollidon VA64 1:20 Pluronic F127 5 wt.-% P2-3-D-4 + Kollidon VA64 1:20Pluronic F127 7.5 wt.-% P2-3-D-5 + Kollidon VA64 1:20 Pluronic F127 10wt.-% P2-3-E-1 + Kollidon VA64 1:24 Pluronic F127 1 wt.-% P2-3-E-2 +Kollidon VA64 1:24 Pluronic F127 2.5 wt.-% P2-3-E-3 + Kollidon VA64 1:24Pluronic F127 5 wt.-% P2-3-E-4 + Kollidon VA64 1:24 Pluronic F127 7.5wt.-% P2-3-E-5 + Kollidon VA64 1:24 Pluronic F127 10 wt.-% P2-4-A-1 +Kollidon VA64 1:8  Myrj 51 1 wt.-% P2-4-A-2 + Kollidon VA64 1:8  Myrj 512.5 wt.-% P2-4-A-3 + Kollidon VA64 1:8  Myrj 51 5 wt.-% P2-4-A-4 +Kollidon VA64 1:8  Myrj 51 7.5 wt.-% P2-4-A-5 + Kollidon VA64 1:8  Myrj51 10 wt.-% P2-4-B-1 + Kollidon VA64 1:12 Myrj 51 1 wt.-% P2-4-B-2 +Kollidon VA64 1:12 Myrj 51 2.5 wt.-% P2-4-B-3 + Kollidon VA64 1:12 Myrj51 5 wt.-% P2-4-B-4 + Kollidon VA64 1:12 Myrj 51 7.5 wt.-% P2-4-B-5 +Kollidon VA64 1:12 Myrj 51 10 wt.-% P2-4-C-1 + Kollidon VA64 1:16 Myrj51 1 wt.-% P2-4-C-2 + Kollidon VA64 1:16 Myrj 51 2.5 wt.-% P2-4-C-3 +Kollidon VA64 1:16 Myrj 51 5 wt.-% P2-4-C-4 + Kollidon VA64 1:16 Myrj 517.5 wt.-% P2-4-C-5 + Kollidon VA64 1:16 Myrj 51 10 wt.-% P2-4-D-1 +Kollidon VA64 1:20 Myrj 51 1 wt.-% P2-4-D-2 + Kollidon VA64 1:20 Myrj 512.5 wt.-% P2-4-D-3 + Kollidon VA64 1:20 Myrj 51 5 wt.-% P2-4-D-4 +Kollidon VA64 1:20 Myrj 51 7.5 wt.-% P2-4-D-5 + Kollidon VA64 1:20 Myrj51 10 wt.-% P2-4-E-1 + Kollidon VA64 1:24 Myrj 51 1 wt.-% P2-4-E-2 +Kollidon VA64 1:24 Myrj 51 2.5 wt.-% P2-4-E-3 + Kollidon VA64 1:24 Myrj51 5 wt.-% P2-4-E-4 + Kollidon VA64 1:24 Myrj 51 7.5 wt.-% P2-4-E-5 +Kollidon VA64 1:24 Myrj 51 10 wt.-% P2-5-A-1 + Kollidon VA64 1:8  Brij98 1 wt.-% P2-5-A-2 + Kollidon VA64 1:8  Brij 98 2.5 wt.-% P2-5-A-3 +Kollidon VA64 1:8  Brij 98 5 wt.-% P2-5-A-4 + Kollidon VA64 1:8  Brij 987.5 wt.-% P2-5-A-5 + Kollidon VA64 1:8  Brij 98 10 wt.-% P2-5-B-1 +Kollidon VA64 1:12 Brij 98 1 wt.-% P2-5-B-2 + Kollidon VA64 1:12 Brij 982.5 wt.-% P2-5-B-3 + Kollidon VA64 1:12 Brij 98 5 wt.-% P2-5-B-4 +Kollidon VA64 1:12 Brij 98 7.5 wt.-% P2-5-B-5 + Kollidon VA64 1:12 Brij98 10 wt.-% P2-5-C-1 + Kollidon VA64 1:16 Brij 98 1 wt.-% P2-5-C-2 +Kollidon VA64 1:16 Brij 98 2.5 wt.-% P2-5-C-3 + Kollidon VA64 1:16 Brij98 5 wt.-% P2-5-C-4 + Kollidon VA64 1:16 Brij 98 7.5 wt.-% P2-5-C-5 +Kollidon VA64 1:16 Brij 98 10 wt.-% P2-5-D-1 + Kollidon VA64 1:20 Brij98 1 wt.-% P2-5-D-2 + Kollidon VA64 1:20 Brij 98 2.5 wt.-% P2-5-D-3 +Kollidon VA64 1:20 Brij 98 5 wt.-% P2-5-D-4 + Kollidon VA64 1:20 Brij 987.5 wt.-% P2-5-D-5 + Kollidon VA64 1:20 Brij 98 10 wt.-% P2-5-E-1 +Kollidon VA64 1:24 Brij 98 1 wt.-% P2-5-E-2 + Kollidon VA64 1:24 Brij 982.5 wt.-% P2-5-E-3 + Kollidon VA64 1:24 Brij 98 5 wt.-% P2-5-E-4 +Kollidon VA64 1:24 Brij 98 7.5 wt.-% P2-5-E-5 + Kollidon VA64 1:24 Brij98 10 wt.-%

Prophetic Examples

Prophetic examples of pharmaceutical dosage forms according to theinvention are provided in the following Table 34. Their compositions areintended to be exemplary and it should be understood that theingredients, the amount thereof and the procedure to obtain the dosageform may be varied.

For example, the ingredients of the following examples may be split upinto intragranular and extragranular ingredients as well as ingredientsfrom which a granulating solution is formed in order to process dosageforms by fluid bed granulation according to inventive example 1; or theymay be processed by an alternative process, such as dry granulation ordirect compression.

TABLE 34 Ingredients [mg] PE-1 PE-2 PE-3 PE-4 PE-5 PE-6 LactoseMonohydrate 69.65 69.65 64.00 64.00 59.65 59.65 Avicel ® (PH101 or PH102) 20.00 20.00 25.00 25.00 30.00 30.00 Croscarmellose sodium 3.00 3.002.50 2.50 3.00 3.00 Compound (I′b) 0.60 0.60 0.30 0.30 0.60 0.60Polyvinyl pyrrolidone 5.00 5.00 5.50 5.50 5.00 5.00 Sodium cetylstearylsulfate 1.00 — 2.00 — 1.00 — Sodium dioctylsulfosuccinate — 1.00 — 2.00— 1.00 Magnesium stearate 0.75 0.75 0.70 0.70 0.75 0.75

Non-Prophetic Examples

The following examples further illustrate the invention but are not tobe construed as limiting its scope.

Example 13

Pharmaceutical dosage forms were manufactured by fluid bed granulationaccording to the following compositions:

TABLE 35 content (dosage: 40 μg) content (dosage: 600 μg) amount peramount per Ingredients wt.-% tablet [mg] % (w/w) tablet [mg]Intragranular Lactose Monohydrate (200M) 50.21 50.21 49.65 49.65 LactoseMonohydrate (100M) 20.00 20.00 20.00 20.00 Avicel ® PH101 10.00 10.0010.00 10.00 Croscarmellose sodium 1.50 1.50 1.50 1.50 GranulatingSolution Compound (I′b) 0.04 0.04 0.6 0.6 Polyvinylpyrrolidone 5.00 5.005.00 5.00 Sodium Lauryl Sulphate 1.00 1.00 1.00 1.00 Purified water — —Extragranular Croscarmellose sodium 1.50 1.50 1.50 1.50 Avicel ® PH10210.00 10.00 10.00 10.00 Magnesium stearate 0.75 0.75 0.75 0.75

Avicel® PH101 and Avicel® PH102 are microcrystalline celluloses withdifferent mean particle sizes (50 and 100 microns). Purified water wasused as part of the granulating fluid, but was removed during thegranulation process.

General Procedure

For the fluid bed granulation process, all intragranular ingredients[lactose monohydrate (200 M and 100 M), Avicel® PH101, croscarmellosesodium] were weighed out and screened through a 710 micron screen into a5 L Pharmatech shell. The material was then blended for 10 minutes at 25rpm using a Pharmatech blender. The granulating solution was prepared bydissolving sodium lauryl sulfate in 600 g of purified water. 400 g ofthe corresponding solution was then used for dissolving thepharmacologically active agent according to formula (I′)(1,1-(3-methylamino-3-phenylpentamethylene)-6-fluoro-1,3,4,9-tetrahydropyrano[3,4-b]indole(trans))and the binder (polyvinylpyrrolidone) to form a drug suspension. Thedrug suspension was top sprayed over the intragranular material at asuitable rate using the Diosna minilab machine to yield compressiblegranules. The compressible granules were then added to the extragranularingredients (croscarmellose sodium, Avicel® PH102, magnesium stearate)and mixed. Compression into tablets was then performed on a single punchManesty F3 compression machine using a 6.00 mm NCCP tooling. The tabletswere coated by means of the polyvinyl alcohol-based coating systemOPADRY® AMB.

For dosage 50 μg, the determined content of the decomposition product6′-fluoro-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohex-3-ene-1,1′-pyrano[3,4-b]indole]after storage at 25° C. and 60% rh as well as after storage at 40° C.and 75% RH was <0.1% after 6 months.

Example 14

Clinical studies were conducted to determine the analgesic efficacy andtolerability of single doses of the compound according to formula (I′b)(200 μg, 400 μg and 600 μg, based on the content of the free base;hemicitrate oral solution of compound (I′b) in Macrogol 400) compared tothat of morphine (60 mg, controlled-released form) and placebo inpatients with acute post-operative pain following orthopedic surgery(bunionectomy).

For this purpose, 258 patients of either sex were included in arandomized, placebo-controlled, double-blind clinical trial in parallelgroups. Treatment groups were well-balanced with respect to demographicsand baseline characteristics with a slight imbalance in baseline painand ethnicity.

After surgery, all patients were initially treated with localpost-operative anesthesia via a popliteal block. Due to differentkinetics of the compound according to formula (I′b) and morphine, thepatients were then treated with either one of the two drugs or withplacebo at slightly different times:

One hour before the popliteal block was stopped, patients wererandomized and part of them were dosed with a single dose of thecompound according to formula (I′b) (200 μg, 400 μg or 600 μg) orplacebo, while the others received morphine or placebo 2 hours after thepopliteal block had been stopped.

The primary efficacy assessment endpoint was the absolute pain intensityover a 24 hour period. Pain intensity was measured using an 11-pointnumerical rating scale (NRS). At each time point, patients wereinstructed to evaluate their current pain intensity relative to an11-point numerical rating scale. A score of zero represented no pain anda score of 10 represented worst possible pain. Missing scheduled painassessments for the patients were imputed with the last observationcarried forward (LOCF). The resulting averaged NRS values over the 24hour period are depicted in FIG. 1.

Sum of pain intensity differences over different time periods wereanalyzed using an analysis of covariance (ANCOVA) model with factors fortreatment and site and baseline pain intensity score (using the painintensity NPRS score). Only subjects with non-missing baseline painintensity were included. A summary of the analysis for the 2 to 10 hourperiod is presented in Table 36. The resulting p-values are summarizedin Table 37.

TABLE 36 LS mean n LS mean SE Δplacebo SE P-value placebo 45 49.13 2.85compound (I′b) 52 46.05 2.78 −3.08 3.49 0.3776 200 μg compound (I′b) 4735.28 2.81 −13.85 3.57 0.0001 400 μg compound (I′b) 55 35.15 2.67 −13.983.45 <0.0001 600 μg morphine, 49 42.01 2.83 −7.12 3.54 0.0454controlled- release 60 mg LS mean: least squares means; SE: statisticalerror

TABLE 37 p-values (sum of pain intensity differences) 2-6 h 2-10 h 2-12h 2-14 h 2-18 h 2-24 h compound (I′b) 0.4514 0.3776 0.3387 0.3427 0.32050.2923 200 μg compound (I′b) 0.0009 0.0001 <0.0001 0.0001 0.0005 0.0008400 μg compound (I′b) 0.0009 <0.0001 <0.0001 <0.0001 <0.0001 0.0001 600μg morphine, 0.4664 0.0454 0.0084 0.0036 0.0014 0.0005 controlled-release 60 mg

Accordingly, on the primary parameter, a statistically significantdifference was observed between groups that had received a 400 μg or 600μg dose of compound (I′b) and placebo groups, whereas no statisticallysignificant difference was observed for groups that had received a 200μg dose of compound (I′b).

Tables 38 and 39 summarize the treatment emergent adverse events(TEAE(s)) experienced by the five treatment groups.

TABLE 38 compound (I′b) compound (I′b) compound (I′b) morphine Placebo200 μg 400 μg 600 μg 60 mg subjects with TEAE(s) (n (%)) 32 (68.1) 37(67.3) 38 (77.6) 48 (84.2) 46 (92.0) related (n (%)) 17 (36.2) 24 (43.6)32 (65.3) 43 (75.4) 42 (84.0) serious (n (%)) 1 (2.1) 0 0 0 0 totalnumber of TEAE's (n) 74 75  125  198  144  related (n (%)) 32 (43.2) 37(49.3) 74 (59.2) 146 (73.7) 99 (68.8) subjects with SAE's 1 (2.1) 0 0 00 Deaths  0 0 0 0 0 TEAE: treatment emergent adverse event; SAE: seriousadverse event

TABLE 39 compound compound compound Pla- (I′b) (I′b) (I′b) morphine cebo200 μg 400 μg 600 μg 60 mg Nausea 17.0 29.1 49.0 64.9 66.0 Vomiting 2.19.1 20.4 49.1 40.0 Dizziness 6.4 20.0 22.4 26.3 24.0 Somnolence 2.1 1.810.2 14.0 16.0 ASAT increased 2.1 1.8 6.1 1.8 2.0 Hot flush 0 1.8 4.17.0 4.0 Pruritus 0 0 6.1 3.5 2.0 Hyperhidrosis 0 0 0 5.3 6.0 100% =total number of subjects in corresponding treatment group; ASAT:aspartate aminotransferase

It becomes evident from Tables 38 and 39 that all four active treatmentswere well tolerated under these circumstances and the adverse eventsthat showed up most frequently are in line with what can be expectedfrom μ-opioid receptor agonists. For the patient group that had beentreated with compound (I′b), the incidence of adverse events increasedwith the dose, and at a dose of 600 μg the incidence of adverse eventswas comparable to that of the morphine patient group.

Example 15

Clinical studies were conducted to determine the bioavailability of atablet formulation containing compound (I′b) in a dose strength of 400μg compared to a hemicitrate oral solution of compound (I′b) (400 μg,400 μg/mL oral solution) in a Macrogol 400 formulation after single oraladministration. 24 healthy white male subjects were included in arandomized, open-label, 3-way crossover, single-center clinical trial.The main pharmacokinetic parameters were AUC_(0-t), AUC_(0-72h) andC_(max).

The results are summarized in Tables 40 to 42.

TABLE 40 pharmaco- kinetic C_(max) AUC_(0-72 h) AUC_(0-t) parametert_(max) [h] [pg/mL] [h · pg/mL] [h · pg/mL] 400 μg/mL 6.00 120 ± 45.92861 ± 1251 4148 ± 2773 oral solution (2.08; 6.00) (38.3%) (43.7%)(66.8%) 400 μg 6.00 135 ± 52.5 3066 ± 1225 4501 ± 2658 Tablet (3.50;10.0) (38.8%) (40.0%) (59.1%) N = 22; The table presents the arithmeticmeans +/− the standard deviation (coefficient of variation).

TABLE 41 Comparison tablets/oral solution C_(max) AUC_(0-72 h) AUC_(0-t)400 μg tablet/ 108% 108% 110% 400 μg/mL oral (101%-118%) (102%-115%)(103%-118%) solution

TABLE 42 total number of subjects Subjects with TEAE(s) TEAE(S) (N) n %e 400 μg tablet 23* 14 60.9 21 400 μg/mL oral 24  19 79.2 40 solution n:number of subjects with at least one TEAE (treatment emergent adverseevent); %: corresponding ratio of subjects experiencing TEAE(s); e:number of TEAE(s); *1-drop out due to unrelated adverse event

Accordingly, the relative bioavailability of the 400 μg tablet and 400μg/mL oral solution based on AUC_(0-72h) was 108%, with 90%-Cl withinthe 80% to 125% range used for assessing bioequivalence.

The relative bioavailability of the 400 μg tablet and 400 μg/mL oralsolution based on C_(max) was also 108%, with 90%-Cl within the 80% to125% range used for assessing bioequivalence.

Single oral dose administrations of 400 μg of compound (I′b) were safeand well tolerated independent from the galenic formulation. No seriousadverse events occurred.

Example 16

Clinical studies were conducted to determine the analgesic efficacy andtolerability of multiple doses of compound (I′b) (40 μg, 80 μg, 100 μg,120 μg and 200 μg; all dosages as weight equivalent dosages relative tothe free base, in the form of the hemicitrate,) compared to that ofmorphine (60 mg, controlled-release) and placebo in patients withpainful diabetic neuropathy.

For this purpose, 86 patients of either sex were included in arandomized, placebo- and dose-controlled, double-blind, triple-crossoverclinical trial in parallel groups.

Three studies with a randomized, double-blind, and cross-over designwere conducted:

-   Study A: Each patient received 2 different doses of compound (I′b)    (40 and 120 μg) and placebo.-   Study B: Each patient received 2 different doses of compound (I′b)    (80 and 200 μg) and placebo.-   Study C: Each patient received 100 μg of compound (I′b), 60 mg    morphine and placebo.

Due to CA request to administer the ‘high dose’ only after exposure ofthe ‘low dose’, in studies A and B only three out of six possiblesequences were applied, whereas in study C all six sequences were usedwith a double dummy administration.

In the first 14 to 18 days of the studies, patients did not receive anytreatment in order to wash out any drugs from former treatment. At theend of this initial phase, pain intensities were determined and patientswere randomized to one of the possible sequences. Then, each patientreceived dose preparations containing the respective dose of compound(I′b), morphine or placebo once daily for 5 days. This phase wasfollowed by an 8 to 10 days long wash-out phase. The remaining two dosepreparations were administered accordingly, i.e. once daily for 5 daysfollowed by a wash-out phase (8 to 10 days).

All treatment groups were well-balanced with respect to demographics andbaseline characteristics, only distribution of gender showed relevantvariations.

The primary endpoint criterion was the reduction from baseline inaverage pain intensity score over the last 24 hours measured with the11-point numerical rating scale (NRS) at the final treatment day of eachtreatment period, in comparison to placebo. Pain assessments were done 5times a day starting at 7 h a.m. almost every 4 hours. At each timepoint, patients were instructed to evaluate their current pain intensityrelative to the 11-point numerical rating scale via e-diary. A score ofzero represented no pain and a score of 10 represented worst possiblepain. Missing scheduled pain assessments for the patients were imputedwith the last observation carried forward (LOCF). The resulting averagedaily pain changes (average change of the NRS value) over the 5-daytreatment periods are depicted in FIGS. 7 to 9.

Pain intensity changes from the period baseline and the overall baselinewere analyzed using descriptive statistics and an analysis of covariance(ANCOVA) model with factors for treatment and site effects, treatmentsequence and period effects, and baseline pain effects. For studies Aand C a period effect was identified. A summary of the descriptivestatistic and ANCOVA analyses is presented in Tables 43, 44 and 45.

TABLE 43 Change from Change from period baseline overall baselinedescriptive descriptive Treatment statistics ANCOVA statistics ANCOVAPlacebo −1.32 −1.62 −1.65 −1.93 40 μg −1.74 −2.25 −1.63 −2.37 compound(I′b) (p = 0.1217) (p = 0.2647) 120 μg −2.18 −1.78 −2.55 −2.04 compound(I′b) (p = 0.7173) (p = 0.7954) TRT effect: p = 0.2979 p = 0.5334 TRTsequence p = 0.7052 p = 0.4140 effect: Period effect: p = 0.0002 p =0.0002 Baseline pain p = 0.0055 p = 0.0053 effect: Centre (site) p =0.0277 p = 0.1982 effect:

TABLE 44 Change from Change from period baseline overall baselinedescriptive descriptive Treatment statistics ANCOVA statistics ANCOVAPlacebo −1.01 −0.99 −1.51 −1.54 80 μg −1.91 −1.78 −2.35 −2.39 compound(I′b) (p = 0.073)  (p = 0.048)  200 μg −1.63 −1.78 −2.74 −2.68 compound(I′b) (p = 0.076)  (p = 0.010)  TRT effect: p = 0.0836 p = 0.0156 TRTsequence p = 0.6471 p = 0.6079 effect: Period effect: p = 0.7325 p =0.8158 Baseline pain p = 0.3784 p = 0.0781 effect:

TABLE 45 Change from Change from period baseline overall baselinedescriptive descriptive Treatment statistics ANCOVA statistics ANCOVAPlacebo −0.93 −1.0 −1.59 −1.5 100 μg −2.01 −1.9 −2.07 −2.0 compound(I′b) (p = 0.0034) (p = 0.1118) 60 μg −2.04 −2.2 −2.27 −2.5 morphine (p< 0.0001) (p = 0.0035) TRT effect: p = 0.0003 p = 0.013  TRT sequence p= 0.1674 p = 0.1803 effect: Period effect: p = 0.0769 p = 0.0004Baseline pain p = 0.0600 p = 0.2223 effect:

According to these results, on the parameter ‘mean daily pain intensitychange from baseline’, all groups that had received compound (I′b) inthe range of 80 μg to 200 μg showed statistically significantdifferences to placebo (except the 120 μg group, most likely due to astrong sequence of treatment effect). For these doses, separation fromplacebo starts at day 1 of administration with increasing effect over 5consecutive days of daily administration. It becomes evident from Table10 and FIG. 9 that for the 100 μg dose of compound (I′b), the analgesiceffect was similar to that of 60 mg morphine. Further, it becomesevident from FIG. 7 that the effect of 40 μg dose of compound (I′b) didnot differentiate from placebo from day 1 onwards, but differentiatedfrom placebo on day 5.

This result is in agreement with the pharmacokinetic parameters thatwere measured in regular time intervals. The arithmetic and geometricmeans of the highest plasma concentration observed after administrationof compound (I′b) on day 5 (C_(max, 5d)) as well as of the arithmeticand geometric means of time needed to reach it after administration ofthis fifth consecutive daily dose (t_(max, 5d)) are summarized in Table11.

TABLE 46 arithmetic mean geometric mean C_(max, 5d)/ C_(max, 5d)/C_(max, 5d) dose t_(max, 5d) C_(max, 5d) dose t_(max, 5d) dosage [pg/mL][mL⁻¹] [h] [pg/mL] [mL⁻¹] [h]  40 μg 27.39 0.68 4.848 25.39 0.63 4.654 80 μg 60.20 0.75 5.150 56.89 0.71 4.783 100 μg 75.24 0.75 5.125 69.170.69 4.658 120 μg 86.49 0.72 4.591 79.81 0.67 4.288 200 μg 160.38 0.805.745 154.68 0.77 5.269

The results of the plasma concentrations measured at 0-3 h afteradministration on day 1, i.e. C_(0-3h, 1d), and at 0-3 h afteradministration on day 5, i.e. C_(0-3h, 5d), are displayed in Table 12(mean±standard deviation, number of subjects N):

TABLE 47 mean dosage C_(0-3 h, 1 d) [pg/mL] C_(0-3 h, 5 d) [pg/mL]  40μg 18.5 ± 18.1 (N = 23)  14.8 ± 8.7 (N = 26)  80 μg 26.5 ± 15.4 (N = 21)40.3 ± 16.4 (N = 22) 100 μg 24.6 ± 19.7 (N = 33) 49.1 ± 27.9 (N = 37)120 μg 34.7 ± 25.8 (N = 26) 50.0 ± 30.6 (N = 25) 200 μg 53.3 ± 40.1 (N =22) 105.2 ± 34.6 (N = 22) 

Table 48 summarizes the plasma concentrations that were measured atdifferent points in time during the five days administration regimen:

TABLE 48 arithmetic mean [pg/ml] geometric mean [pg/ml] 0.5-3 h 3-8 h0.5-3 h 3-8 h dosage day 1 day 5 day 3 day 5 day 1 day 5 day 3 day 5  40μg 18.47 14.84 23.42 26.83 13.53 12.69 21.40 24.66  80 μg 26.46 40.3356.87 58.56 21.61 37.00 55.22 55.36 100 μg 24.58 49.14 74.03 72.79 18.0242.41 66.13 66.64 120 μg 34.64 49.97 78.46 84.65 24.51 41.47 72.84 78.10200 μg 53.33 105.21 153.31 154.27 40.00 99.43 148.86 147.69 arithmeticmean [ng/ml] geometric mean [ng/ml] dosage morphine 0.5-3 h 3-8 h 0.5-3h 3-8 h controlled release day 1 day 5 day 3 day 5 day 1 day 5 day 3 day5 60 mg 5.00 7.39 9.54 11.36 3.83 6.20 7.70 9.87

FIG. 10 shows a comparison of the mean C_(max) values measured on day 5in comparison to the plasma concentration that was observed before thenext dose was administered (C_(next predose)), i.e. 8 to 10 days afteradministration of the fifth dose at the end of the wash-out phase.

It is evident from FIG. 10 that samples taken 8-10 days after previoustreatment with compound (I′b) still contained this drug in detectable(and statistically relevant) concentrations. Even samples taken 10-15days after previous treatment with compound (I′b) still hadconcentrations >2.0 pg/mL.

Tables 49 and 50 summarize the treatment emergent adverse events(TEAE(s)) experienced by the treatment groups.

TABLE 49 60 mg Placebo Placebo Placebo 40 μg 80 μg 100 μg 120 μg 200 μgMorphine Population Study A Study B Study C Study A Study B Study CStudy A Study B Study C Total 26 23 36 26 23 37 26 23 36 number ofsubjects Subjects 17 (65.4%) 16 (69.6%) 25 (69.4%) 21 (80.8%) 16 (69.6%)27 (73%) 17 (65.4%) 19 (82.6%)  34 (94.4%) with TEAEs Total 62 (34) 42(21) 69 (57) 65 (39) 53 (24) 91 (52) 54 (36) 91 (76) 209 (156) number ofTEAEs^(a)) Number of  0  0  1*  0  0  0  0  0  0 serious TEAEs Number of 0  0  1  0  0  0  0  0  3 events leading to withdrawalTEAEs^(a))treatment emergent adverse event (at least possibly related);*vitreous heamorrhage, patient with medical history of diabeticretinopathy

TABLE 50 60 mg Placebo Placebo Placebo 40 μg 80 μg 100 μg 120 μg 200 μgMorphine TEAEs (%) Study A Study B Study C Study A Study B Study C StudyA Study B Study C Nausea 19.2 17.4 16.7 26.9 13.0 13.5 23.1 39.1 47.2Headache 23.1 17.4 5.6 34.6 13.0 8.1 23.1 17.4 25.0 Dizziness 11.5 13.011.1 26.9 26.1 18.9 23.1 34.8 19.4 Constipation 11.5 8.7 8.3 23.1 0 16.27.7 4.3 25.0 Fatigue 19.2 4.3 2.8 11.5 4.3 13.5 3.8 21.7 19.4 Vomiting3.8 0 8.3 0 4.3 13.5 7.7 13.0 52.8 Vision blurred 0 4.3 0 0 4.3 2.7 013.0 0 Visual 0 4.3 0 0 0 2.7 0 8.7 0 impairment Pruritus 0 0 2.8 0 010.8 0 0 13.9 Cold sweat 0 0 0 0 8.7 2.7 0 4.3 0 Hyperglycemia 0 4.3 0 08.7 2.7 3.8 0 2.8 ECG QT 0 4.3 0 0 8.7 0 3.8 0 0 prolonged Bacteriuria 00 13.9 0 8.7 10.8 0 0 13.9 Peripheral 3.8 0 2.8 7.7 0 0 3.8 0 0 oedemaOral 3.8 0 0 7.7 0 0 0 0 0 discomfort Oropharyngeal 3.8 0 2.8 0 0 5.6 00 8.1 Pain Dyspepsia 3.8 4.3 2.8 7.7 4.3 5.4 0 0 2.8 Back pain 0 0 2.87.7 0 0 0 0 5.6

It is evident from Tables 49 and 50 that doses up to 120 μg of compound(I′b) had a incidence of treatment emergent adverse events (TEAEs)similar to placebo with the exception of dizziness which was reportedmore frequently compared to placebo at all doses examined. Typicaladverse events expected from μ-opioid receptor agonists were starting tobe present only at the top dose of 200 μg. There were clearly more TEAEsreported following administration of 60 mg Morphine compared to 100 μgof compound (I′b) paired with a comparable analgesic efficacy (cf. Table10 and FIG. 9).

The foregoing description and examples have been set forth merely toillustrate the invention and are not intended to be limiting. Sincemodifications of the described embodiments incorporating the spirit andsubstance of the invention may occur to persons skilled in the art, theinvention should be construed broadly to include all variations withinthe scope of the appended claims and equivalents thereof.

1. A pharmaceutical dosage form for use in the treatment of pain, whichcontains a pharmacologically active agent corresponding to formula (I)

wherein R is —H or —CH₃, or a physiologically acceptable salt thereof,and wherein the pharmaceutical dosage form is administered twice daily,once daily or less frequently.
 2. The pharmaceutical dosage formaccording to claim 1, wherein said dosage form provides immediaterelease in vitro of the pharmacologically active agent corresponding toformula (I) in accordance with Ph. Eur.
 3. The pharmaceutical dosageform according to claim 1, wherein the pharmacologically active agentcorresponding to formula (I) is molecularly dispersed.
 4. Thepharmaceutical dosage form according to claim 1, which comprises aliquid core encapsulated by a solid material, wherein thepharmacologically active agent corresponding to formula (I) is dispersedin the liquid core.
 5. The pharmaceutical dosage form according to claim1, wherein said dosage form contains a self-emulsifying formulationgiving (micro)emulsions with an average droplet size smaller than orequal 10 micrometers in presence of aqueous media.
 6. The pharmaceuticaldosage form according to claim 1, further comprising a surfactant. 7.The pharmaceutical dosage form according to claim 6, wherein thesurfactant has a HLB value of at least 10; and/or the content of thesurfactant is at least 0.001 wt.-%, based on the total weight of thepharmaceutical dosage form.
 8. The pharmaceutical dosage form accordingto claim 6, wherein the surfactant is selected from the group consistingof polyoxyethylene fatty acid esters, partial fatty acid esters ofpolyoxyethylenesorbitan, and sulfuric acid esters.
 9. The pharmaceuticaldosage form according to claim 1, wherein the pharmacologically activeagent corresponding to formula (I) has a stereochemistry according toformula (I′)

wherein R is —H or —CH₃.
 10. The pharmaceutical dosage form according toclaim 1, wherein the pharmacologically active agent corresponding toformula (I) is(1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amine,(1r,4r)-6′-fluoro-N-methyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amine,or a physiologically acceptable salt thereof.
 11. The pharmaceuticaldosage form according to claim 1, wherein under in vitro conditions in900 mL artificial gastric juice at pH 1.2 said dosage form releasesafter 30 minutes at least 80 wt.-% of the pharmacologically active agentcorresponding to formula (I), based on the total amount of thepharmacologically active agent corresponding to formula (I) originallycontained in the dosage form.
 12. The pharmaceutical dosage formaccording to claim 1, wherein said dosage form contains thepharmacologically active agent corresponding to formula (I) in a dose offrom 10 μg to 50 μg.
 13. The pharmaceutical dosage form according toclaim 1, wherein said dosage form contains the pharmacologically activeagent corresponding to formula (I) in a dose of from 300 μg to 500 μg.14. The pharmaceutical dosage form according to claim 1, wherein: thepharmacokinetic parameter t_(max) is within the range of from 0.5 to 16h; and/or the ratio of the pharmacokinetic parameter AUC_(0-t)/dose iswithin the range of from 0.3 to 20 h/m³; and/or the ratio of thepharmacokinetic parameter C_(max)/dose is within the range of from 0.04to 2.00 m⁻³.
 15. The pharmaceutical dosage form according to claim 1,wherein the pain is selected from the group consisting of acute pain,visceral pain, neuropathic pain, and chronic pain.
 16. A pharmaceuticaldosage form for administration twice daily, once daily or lessfrequently, which contains a pharmacologically active agentcorresponding to formula (I)

wherein R is —H or —CH₃, or a physiologically acceptable salt thereof;and wherein in accordance with Ph. Eur. under in vitro conditions in 900mL artificial gastric juice at pH 1.2 and 37±0.5° C. said dosage formreleases after 30 minutes according to the paddle method with sinker at100 rpm at least 50 wt.-% of the pharmacologically active agent, basedon the total amount of the pharmacologically active agent originallycontained in the pharmaceutical dosage form.
 17. The pharmaceuticaldosage form according to claim 16, wherein the pharmacologically activeagent corresponding to formula (I) is molecularly dispersed.
 18. Thepharmaceutical dosage form according to claim 16, wherein said dosageform comprises a solid polymeric matrix material in which thepharmacologically active agent corresponding to formula (I) isdispersed.
 19. The pharmaceutical dosage form according to claim 16,wherein said dosage form comprises a polymer selected from the groupconsisting of polyvinylpyrrolidone, vinylpyrrolidone-polyvinylacetatecopolymers, cellulose derivatives, polymethacrylates, polyethyleneoxides, polyethylene glycols and any combinations thereof.
 20. Thepharmaceutical dosage form according to claim 16, further comprising asurfactant.
 21. The pharmaceutical dosage form according to claim 20,wherein the surfactant has a HLB value of at least 10; and/or thecontent of the surfactant is at least 0.001 wt.-%, based on the totalweight of the pharmaceutical dosage form.
 22. The pharmaceutical dosageform according to claim 20, wherein the surfactant is selected from thegroup consisting of polyoxyethylene fatty acid esters, partial fattyacid esters of polyoxyethylenesorbitan, and sulfuric acid esters. 23.The pharmaceutical dosage form according to claim 16, wherein thepharmacologically active agent corresponding to formula (I) has astereochemistry corresponding to formula (I′)

wherein R is —H or —CH₃.
 24. The pharmaceutical dosage form according toclaim 16, wherein the pharmacologically active agent corresponding toformula (I) is(1r,40-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amine,(1r,4r)-6′-fluoro-N-methyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amine,or a physiologically acceptable salt thereof.
 25. The pharmaceuticaldosage form according to claim 16, wherein under in vitro conditions in900 mL artificial gastric juice at pH 1.2 said dosage form releasesafter 30 minutes at least 80 wt.-% of the pharmacologically active agentcorresponding to formula (I), based on the total amount of thepharmacologically active agent corresponding to formula (I) originallycontained in the dosage form.
 26. The pharmaceutical dosage formaccording to claim 16, wherein said dosage form contains thepharmacologically active agent corresponding to formula (I) in a dose offrom 10 μg to 50 μg.
 27. The pharmaceutical dosage form according toclaim 16, wherein said dosage form contains the pharmacologically activeagent corresponding to formula (I) in a dose of from 300 μg to 500 μg.28. The pharmaceutical dosage form according to claim 16, wherein thepharmacokinetic parameter t_(max) is within the range of from 0.5 to 16h; and/or the ratio of the pharmacokinetic parameter AUC_(0-t)/dose iswithin the range of from 0.3 to 20 h/m³; and/or the ratio of thepharmacokinetic parameter C_(max)/dose is within the range of from 0.04to 2.00 m⁻³.
 29. A method of treating pain in a subject in need thereof,said method comprising administering to said subject twice daily, oncedaily or less frequently a pharmaceutical dosage form according to claim16.
 30. A method according to claim 29, wherein the pain is selectedfrom the group consisting of acute pain, visceral pain, neuropathic painand chronic pain.
 31. A pharmaceutical dosage form for administrationtwice daily, once daily or less frequently, which contains apharmacologically active agent corresponding to formula (I)

wherein R is —H or —CH₃, or a physiologically acceptable salt thereof.32. The pharmaceutical dosage form according to claim 31, wherein saiddosage form provides immediate release in vitro of the pharmacologicallyactive agent corresponding to formula (I) in accordance with Ph. Eur.33. The pharmaceutical dosage form according to claim 31, wherein saiddosage form is a tablet.
 34. The pharmaceutical dosage form according toclaim 31, further comprising at least one pharmaceutical excipientselected from the group consisting of antiadherents, binders,disintegrants, fillers, diluents, glidants, lubricants andpreservatives.
 35. The pharmaceutical dosage form according to claim 31,further comprising a surfactant.
 36. The pharmaceutical dosage formaccording to claim 35, wherein the surfactant has a HLB value of atleast 10; and/or the content of the surfactant is at least 0.001 wt.-%,based on the total weight of the pharmaceutical dosage form.
 37. Thepharmaceutical dosage form according to claim 35, which is prepared bywet granulation from an aqueous granulating fluid containing thepharmacologically active agent corresponding to formula (I) and thesurfactant.
 38. The pharmaceutical dosage form according to claim 35,wherein the surfactant is selected from the group consisting ofpolyoxyethylene fatty acid esters, partial fatty acid esters ofpolyoxyethylenesorbitan, and sulfuric acid esters.
 39. Thepharmaceutical dosage form according to claim 31, wherein thepharmacologically active agent corresponding to formula (I) has astereochemistry according to formula (I′)

wherein R is —H or —CH₃.
 40. The pharmaceutical dosage form according toclaim 31, wherein the pharmacologically active agent corresponding toformula (I) is(1r,40-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amine,(1r,4r)-6′-fluoro-N-methyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amine,or a physiologically acceptable salt thereof.
 41. The pharmaceuticaldosage form according to claim 31, wherein under in vitro conditions in900 mL artificial gastric juice at pH 1.2 said dosage form releasesafter 30 minutes at least 80 wt.-% of the pharmacologically active agentcorresponding to formula (I), based on the total amount of thepharmacologically active agent corresponding to formula (I) originallycontained in the dosage form.
 42. The pharmaceutical dosage formaccording to claim 31, wherein said dosage form contains thepharmacologically active agent corresponding to formula (I) in a dose offrom 10 μg to 50 μg.
 43. The pharmaceutical dosage form according toclaim 31, wherein said dosage form contains the pharmacologically activeagent corresponding to formula (I) in a dose of from 300 μg to 500 μg.44. The pharmaceutical dosage form according to claim 31, wherein thepharmacokinetic parameter t_(max) is within the range of from 0.5 to 16h; and/or the ratio of the pharmacokinetic parameter AUC_(0-t)/dose iswithin the range of from 0.3 to 20 h/m³; and/or the ratio of thepharmacokinetic parameter C_(max)/dose is within the range of from 0.04to 2.00 m⁻³.
 45. A method of treating pain in a subject in need thereof,said method comprising administering to said subject twice daily, oncedaily or less frequently a pharmaceutical dosage form according to claim31.
 46. A method according to claim 45, wherein the pain is selectedfrom the group consisting of acute pain, visceral pain, neuropathic painand chronic pain.
 47. A pharmaceutical dosage form for administrationonce daily containing a pharmacologically active agent corresponding toformula (I)

wherein R is —H or —CH₃, or a physiologically acceptable salt thereof,and wherein said dosage form: provides immediate release in vitro of thepharmacologically active agent corresponding to formula (I) inaccordance with Ph. Eur.; contains the pharmacologically active agentcorresponding to formula (I) in a dose of from 10 μg to 190 μg; andexhibits a pharmacokinetic parameter t_(max) within the range of from0.5 to 16 h.
 48. The pharmaceutical dosage form according to claim 47,wherein said dosage form contains the pharmacologically active agentcorresponding to formula (I) in a dose of from 25 μg to 80 μg.
 49. Thepharmaceutical dosage form according to claim 47, wherein said dosageform contains the pharmacologically active agent corresponding toformula (I) in a dose of from 10 μg to 50 μg.
 50. The pharmaceuticaldosage form according to claim 47, wherein the pharmacologically activeagent corresponding to formula (I) has a stereochemistry correspondingto formula (I′)

wherein R is —H or —CH₃.
 51. The pharmaceutical dosage form according toclaim 47, wherein the pharmacologically active agent corresponding toformula (I) is(1r,40-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amine,(1r,4r)-6′-fluoro-N-methyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amine,or a physiologically acceptable salt thereof.
 52. The pharmaceuticaldosage form according to claim 47, wherein under in vitro conditions in900 mL artificial gastric juice at pH 1.2 said dosage form releasesafter 30 minutes at least 80 wt.-% of the pharmacologically active agentcorresponding to formula (I), based on the total amount of thepharmacologically active agent corresponding to formula (I) originallycontained in the dosage form.
 53. The pharmaceutical dosage formaccording to claim 47, wherein said dosage form contains thepharmacologically active agent corresponding to formula (I) in an amountthat is sub-therapeutic with regard to a single administration of thedosage form.
 54. The pharmaceutical dosage form according to claim 47,wherein said dosage form contains the pharmacologically active agentcorresponding to formula (I) in a quantity that is sub-therapeutic withregard to acute pain treatment.
 55. The pharmaceutical dosage formaccording to claim 47, wherein said dosage form contains thepharmacologically active agent corresponding to formula (I) in aquantity such that initial dose titration is not required.
 56. Thepharmaceutical dosage form according to claim 47, wherein said dosageform has a pharmacokinetic parameter t_(max) within the range of from 2to 10 h.
 57. The pharmaceutical dosage form according to claim 47,wherein said dosage form has a pharmacokinetic parameter AUC_(0-t)/dosewithin the range of from 0.3 to 20 h/m³.
 58. The pharmaceutical dosageform according to claim 47, wherein said dosage form has apharmacokinetic parameter C_(max)/dose within the range of from 0.04 to2.00 m⁻³.
 59. The pharmaceutical dosage form according to claim 47,wherein after once daily administration of the pharmaceutical dosageform to a subject for at least 5 consecutive days, said dosage formproduces in said subject a highest plasma concentration of thepharmacological agent within the range from 10 to 120 μg/m³.
 60. Thepharmaceutical dosage form according to claim 59, wherein the highestplasma concentration of the pharmacological agent reached after oncedaily administration of the pharmaceutical dosage form to said subjectfor at least 5 consecutive days is within the range from 20 to 80 μg/m³.61. The pharmaceutical dosage form according to claim 59, wherein thetime to reach the highest plasma concentration of the pharmacologicalagent reached after once daily administration of the pharmaceuticaldosage form for at least 5 consecutive days is within the range of from2 to 6 h.
 62. A method of treating neuropathic pain in a subject in needthereof, said method comprising administering once daily to said subjecta pharmaceutical dosage form according to claim
 47. 63. A pharmaceuticaldosage form for administration once daily and containing apharmacologically active agent corresponding to formula (I)

wherein R is —H or —CH₃, or a physiologically acceptable salt thereof,and wherein said dosage form provides immediate release in vitro of thepharmacologically active agent corresponding to formula (I) inaccordance with Ph. Eur.; and contains the pharmacologically activeagent corresponding to formula (I) in a dose of from 150 μg to 800 μg;and has a pharmacokinetic parameter t_(max) within the range of from 0.5to 16 h.
 64. The pharmaceutical dosage form according to claim 63,wherein said dosage form contains the pharmacologically active agentcorresponding to formula (I) in a dose of from 200 μg to 600 μg.
 65. Thepharmaceutical dosage form according to claim 64, wherein said dosageform contains the pharmacologically active agent corresponding toformula (I) in a dose of from 300 μg to 500 μg.
 66. The pharmaceuticaldosage form according to claim 63, wherein the pharmacologically activeagent corresponding to formula (I) has a stereochemistry correspondingto formula (I′)

wherein R is —H or —CH₃.
 67. The pharmaceutical dosage form according toclaim 63, wherein the pharmacologically active agent corresponding toformula (I) is(1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amine,(1r,4r)-6′-fluoro-N-methyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amine,or a physiologically acceptable salt thereof.
 68. The pharmaceuticaldosage form according to claim 63, wherein under in vitro conditions in900 mL artificial gastric juice at pH 1.2 said dosage form releasesafter 30 minutes at least 80 wt.-% of the pharmacologically active agentcorresponding to formula (I), based on the total amount of thepharmacologically active agent corresponding to formula (I) originallycontained in the dosage form.
 69. The pharmaceutical dosage formaccording to claim 63, wherein said dosage form has a pharmacokineticparameter t_(max) within the range of from 2 to 10 h.
 70. Thepharmaceutical dosage form according to claim 63, wherein said dosageform has a pharmacokinetic parameter AUC_(0-t)/dose within the range offrom 0.3 to 20 h/m³.
 71. The pharmaceutical dosage form according toclaim 63, wherein said dosage form has a pharmacokinetic parameterC_(max)/dose within the range of from 0.04 to 2.00 m⁻³.
 72. A method oftreating nociceptive pain in a subject in need thereof, said methodcomprising administering once daily to said subject a pharmaceuticaldosage form according to claim
 63. 73. The method according to claim 72,wherein said nociceptive pain is selected from the group consisting ofacute nociceptive pain and chronic nociceptive pain.
 74. The methodaccording to claim 72, wherein said nociceptive pain is selected fromthe group consisting of somatic pain and visceral pain.
 75. Thepharmaceutical dosage form according to claim 33, wherein thepharmacologically active agent is(1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amineor a physiologically acceptable salt thereof, and wherein the tabletfurther comprises one or more fillers in an amount from 0.001 to 90wt.-% and one or more binders in an amount from 0.1 to 25 wt.-%.
 76. Thepharmaceutical dosage form according to claim 75, wherein the tabletfurther comprises from one or more antiadherents in an amount from 0.001to 5.0 wt.-%, one or more lubricants in an amount from 0.001 to 5 wt.-%,and/or one or more disintegrants in an amount from 0.001 to 5 wt.-%. 77.The pharmaceutical dosage form according to claim 76, wherein the tabletcomprises about 50 μg, about 200 μg, about, 400 μg, or about 600 μg of(1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amineor physiologically acceptable salt.
 78. The pharmaceutical dosage formaccording to claim 77, wherein the T_(max) is within the range of from0.5 to 16 h; and/or the ratio of the pharmacokinetic parameterAUC_(0-t)/dose is within the range of from 0.3 to 20 h/m³; and/or theratio of the pharmacokinetic parameter C_(max)/dose is within the rangeof from 0.04 to 2.00 m⁻³.
 79. A method of treating pain in a subject inneed thereof, said method comprising administering to said subject twicedaily, once daily or less frequently a pharmaceutical dosage formaccording to claim
 77. 80. A method according to claim 79, wherein thepain is selected from the group consisting of chronic nociceptive pain,chronic neuropathic pain and acute pain.